ABSTRACT

Cholesterol and triglycerides are insoluble in water and therefore these lipids must be transported in association with proteins. Lipoproteins are complex particles with a central core containing cholesterol esters and triglycerides surrounded by free cholesterol, phospholipids, and apolipoproteins, which facilitate lipoprotein formation and function. Plasma lipoproteins can be divided into seven classes based on size, lipid composition, and apolipoproteins (chylomicrons, chylomicron remnants, VLDL, VLDL remnants (IDL), LDL, HDL, and Lp (a)).  Chylomicron remnants, VLDL, IDL, LDL, and Lp (a) are all pro-atherogenic while HDL is anti-atherogenic. Apolipoproteins have four major functions including 1) serving a structural role, 2) acting as ligands for lipoprotein receptors, 3) guiding the formation of lipoproteins, and 4) serving as activators or inhibitors of enzymes involved in the metabolism of lipoproteins. The exogenous lipoprotein pathway starts with the incorporation of dietary lipids into chylomicrons in the intestine. In the circulation, the triglycerides carried in chylomicrons are metabolized in muscle and adipose tissue by lipoprotein lipase releasing free fatty acids, which are subsequently metabolized by muscle and adipose tissue, and chylomicron remnants are formed. Chylomicron remnants are then taken up by the liver. The endogenous lipoprotein pathway begins in the liver with the formation of VLDL. The triglycerides carried in VLDL are metabolized in muscle and adipose tissue by lipoprotein lipase releasing free fatty acids and IDL are formed. The IDL are further metabolized to LDL, which are taken up by the LDL receptor in numerous tissues including the liver, the predominant site of uptake. Reverse cholesterol transport begins with the formation of nascent HDL by the liver and intestine. These small HDL particles can then acquire cholesterol and phospholipids that are effluxed from cells, a process mediated by ABCA1 resulting in the formation of mature HDL.  Mature HDL can acquire addition cholesterol from cells via ABCG1, SR-B1, or passive diffusion. The HDL then transports the cholesterol to the liver either directly by interacting with hepatic SR-B1 or indirectly by transferring the cholesterol to VLDL or LDL, a process facilitated by CETP. Cholesterol efflux from macrophages to HDL plays an important role in protecting from the development of atherosclerosis.

INTRODUCTION

Because lipids, such as cholesterol and triglycerides, are insoluble in water these lipids must be transported in association with proteins (lipoproteins) in the circulation. Large quantities of fatty acids from meals must be transported as triglycerides to avoid toxicity. These lipoproteins play a key role in the absorption and transport of dietary lipids by the small intestine, in the transport of lipids from the liver to peripheral tissues, and the transport of lipids from peripheral tissues to the liver and intestine (reverse cholesterol transport). A secondary function is to transport toxic foreign hydrophobic and amphipathic compounds, such as bacterial toxins, from areas of invasion and infection (1). For example, lipoproteins bind endotoxin (LPS) from gram negative bacteria and lipoteichoic acid from gram positive bacteria thereby reducing their toxic effects (1). In addition, apolipoprotein L1, associated with HDL particles, has lytic activity against the parasite Trypanosoma brucei brucei and lipoproteins can neutralize viruses (2,3). Thus, while this article will focus on the transport properties of lipoproteins the reader should recognize that lipoprotein may have other important roles.

STRUCTURE OF LIPOPROTEINS (4)

Figure 1. Lipoprotein Structure (figure modified from Biochemistry 39: 9763, 2000)

Figure 2: Classes of Lipoproteins (figure modified from Advances Protein Chemistry 45:303, 1994)

Chylomicrons (5)

These are large triglyceride rich particles made by the intestine, which are involved in the transport of dietary triglycerides and cholesterol to peripheral tissues and liver. These particles contain apolipoproteins A-I, A-II, A-IV, A-V, B-48, C-II, C-III, and E. Apo B-48 is the core structural protein and each chylomicron particle contains one Apo B-48 molecule. The size of chylomicrons varies depending on the amount of fat ingested. A high fat meal leads to the formation of large chylomicron particles due to the increased amount of triglyceride being transported whereas in the fasting state the chylomicron particles are small carrying decreased quantities of triglyceride. The quantity of cholesterol carried by chylomicrons also can vary depending upon dietary intake.

Chylomicron Remnants (5-7)

The removal of triglyceride from chylomicrons by lipoprotein lipase in peripheral tissues results in smaller particles called chylomicron remnants. Compared to chylomicrons these particles are enriched in cholesterol and are pro-atherogenic.

Very Low-Density Lipoproteins (VLDL)

These particles are produced by the liver and are triglyceride rich. They contain apolipoprotein B-100, C-I, C-II, C-III, and E. Apo B-100 is the core structural protein and each VLDL particle contains one Apo B-100 molecule. Similar to chylomicrons the size of the VLDL particles can vary depending on the quantity of triglyceride carried in the particle. When triglyceride production in the liver is increased, the secreted VLDL particles are large. However, VLDL particles are smaller than chylomicrons.

Intermediate-Density Lipoproteins (IDL; VLDL Remnants) (6,7)

The removal of triglycerides from VLDL by muscle and adipose tissue results in the formation of IDL particles which are enriched in cholesterol. These particles contain apolipoprotein B-100 and E. These IDL particles are pro-atherogenic.

Low-Density Lipoproteins (LDL)

These particles are derived from VLDL and IDL particles and they are even further enriched in cholesterol. LDL carries the majority of the cholesterol that is in the circulation. The predominant apolipoprotein is B-100 and each LDL particle contains one Apo B-100 molecule. LDL consists of a spectrum of particles varying in size and density. An abundance of small dense LDL particles is seen in association with hypertriglyceridemia, low HDL levels, obesity, type 2 diabetes (i.e. patients with the metabolic syndrome) and infectious and inflammatory states. These small dense LDL particles are considered to be more pro-atherogenic than large LDL particles for a number of reasons (8). Small dense LDL particles have a decreased affinity for the LDL receptor resulting in a prolonged retention time in the circulation. Additionally, they more easily enter the arterial wall and bind more avidly to intra-arterial proteoglycans, which traps them in the arterial wall. Finally, small dense LDL particles are more susceptible to oxidation, which could result in an enhanced uptake by macrophages. 

High-Density Lipoproteins (HDL) (9-11)

These particles play an important role in reverse cholesterol transport from peripheral tissues to the liver, which is one potential mechanism by which HDL may be anti-atherogenic. In addition, HDL particles have anti-oxidant, anti-inflammatory, anti-thrombotic, and anti-apoptotic properties, which may also contribute to their ability to inhibit atherosclerosis. HDL particles are enriched in cholesterol and phospholipids. Apolipoproteins A-I, A-II, A-IV, C-I, C-II, C-III, and E are associated with these particles. Apo A-I is the core structural protein and each HDL particle may contain multiple Apo A-I molecules. In addition, using mass spectrometry proteins involved in proteinase inhibition, complement activation, and the acute-phase response have been found associated with HDL particles (12). HDL particles are very heterogeneous and can be classified based on density, size, charge, or apolipoprotein composition (Table 2).

Lipoprotein (a) (Lp (a)) (13-16)

Lp (a) is an LDL particle that has apolipoprotein (a) attached to Apo B-100 via a disulfide bond. Lp (a) contain Apo (a) and Apo B-100 in a 1:1 molar ratio. The size of Lp(a) particles can vary greatly based on the size of apolipoprotein (a). This particle is pro-atherogenic.

APOLIPOPROTEINS (17,18)

Apolipoproteins have four major functions including 1) serving a structural role, 2) acting as ligands for lipoprotein receptors, 3) guiding the formation of lipoproteins, and 4) serving as activators or inhibitors of enzymes involved in the metabolism of lipoproteins (Table 3). Apolipoproteins thus play a crucial role in lipoprotein metabolism.

Apolipoprotein A-I (19)

Apo A-I is synthesized in the liver and intestine and is the major structural protein of HDL accounting for approximately 70% of HDL protein. It also plays a role in the interaction of HDL with ATP-binding cassette protein A1 (ABCA1), ABCG1, and class B, type I scavenger receptor (SR-B1). Apo A-I is an activator of lecithin: cholesterol acyltransferase (LCAT), an enzyme that converts free cholesterol into cholesteryl ester. High levels of Apo A-I are associated with a decreased risk of atherosclerosis.

Apolipoprotein A-II (20)

Apo A-II is synthesized in the liver and is the second most abundant protein on HDL accounting for approximately 20% of HDL protein. The role of Apo A-II in lipid metabolism is unclear. Apo A-II is a strong predictor of risk for CVD.

Apolipoprotein A-IV (21)

Apo A-IV is synthesized in the intestine during fat absorption. Apo A-IV is associated with chylomicrons and high-density lipoproteins, but is also found in the lipoprotein-free fraction.  Its precise role in lipoprotein metabolism remains to be determined but studies have suggested a role for Apo A-IV in regulating food intake.

Apolipoprotein A-V (22,23)

Apo A-V is synthesized in the liver and associates with triglyceride rich lipoproteins. It is an activator of LPL mediated lipolysis and thereby plays an important role in the metabolism of triglyceride rich lipoproteins.

Apolipoprotein B-48 (24)

Apo B-48 is synthesized in the intestine and is the major structural protein of chylomicrons and chylomicron remnants. There is a single molecule of apo B-48 per chylomicron particle. There is a single apolipoprotein B gene that is expressed in both the liver and intestine. The intestine expresses a protein that is approximately ½ the size of the liver due to mRNA editing. The apobec-1 editing complex is expressed in the intestine and edits a specific cytidine to an uracil in the apo B mRNA in the intestine creating a stop codon that results in the cessation of protein translation and a shorter Apo B (Apo B-48). The portion of Apo-B that is recognized by the LDL receptor is not contained in Apo-B48 and therefore Apo B-48 is not recognized by the LDL receptor.

Apolipoprotein B-100

Apo B-100 is synthesized in the liver and is the major structural component of VLDL, IDL, and LDL. There is a single molecule of Apo B-100 per VLDL, IDL, LDL and Lp(a) particle. Apo B-100 is a ligand for the LDL receptor and therefore plays an important role in the clearance of lipoprotein particles. Certain mutations in Apo B-100 result in decreased binding to the LDL receptor and familial hypercholesterolemia (25). High levels of Apo B-100 are associated with an increased risk of atherosclerosis.

Apolipoprotein C (26-29)

The C apolipoproteins are synthesized primarily in the liver and freely exchange between lipoprotein particles and therefore are found in association with chylomicrons, VLDL, and HDL.

Apo C-II is a co-factor for lipoprotein lipase (LPL) and thus stimulates triglyceride hydrolysis and the clearance of triglyceride rich lipoproteins (26,29). Loss of function mutations in Apo C-II result in marked hypertriglyceridemia due to a failure to metabolize triglyceride rich lipoproteins (30).

Apo C-III is an inhibitor of LPL (31). Additionally, Apo C-III inhibits the interaction of triglyceride rich lipoproteins with their receptors (31). Recent studies have shown that loss of function mutations in Apo C-III lead to decreases in serum triglyceride levels and a reduced risk of cardiovascular disease. Interestingly, inhibition of Apo C-III expression results in a decrease in serum triglyceride levels even in patients deficient in lipoprotein lipase indicating that the ability of Apo C-III to modulate serum triglyceride levels is not dependent solely on regulating lipoprotein lipase activity (32).

Apolipoprotein E (33)

Apolipoprotein E is synthesized in many tissues but the liver and intestine are the primary source of circulating Apo E. Apo E exchanges between lipoprotein particles and is associated with chylomicrons, chylomicron remnants, VLDL, IDL, and a subgroup of HDL particles. There are three common genetic variants of Apo E (Apo E2, E3, and E4). ApoE2 differs from the most common isoform, Apo E3, by a single amino acid substitution where cysteine substitutes for arginine at residue 158. Apo E4 differs from Apo E3 at residue 112, where arginine substitutes for cysteine. Apo E3 and E4 are ligands for the LDL receptor while Apo E2 is poorly recognized by the LDL receptor. Patients who are homozygous for Apo E2 can develop familial dysbetalipoproteinemia (30). Apo E4 is associated with an increased risk of Alzheimer’s disease and an increased risk of atherosclerosis.

Apolipoprotein (a) (14,16)

Apo (a) is synthesized in the liver. This protein is a homolog of plasminogen and its molecular weight varies from 300,000 to 800,000. It is attached to Apo B-100 via a disulfide bond. High levels of Apo (a) are associated with an increased risk of atherosclerosis. Apo (a) is an inhibitor of fibrinolysis and can also enhance the uptake of lipoproteins by macrophages, both of which could increase the risk of atherosclerosis. The physiologic function of Apo (a) is unknown. Interestingly this apolipoprotein is found in primates but not in other species.

LIPOPROTEIN RECEPTORS AND LIPID TRANSPORTERS

There are several receptors and transporters that play a crucial role in lipoprotein metabolism.

LDL Receptor (34)

The LDL receptor is present in the liver and most other tissues. It recognizes Apo B-100 and Apo E and hence mediates the uptake of LDL, chylomicron remnants, and IDL, which occurs via endocytosis (Figure 3). After internalization, the lipoprotein particle is degraded in lysosomes and the cholesterol is released. The delivery of cholesterol to the cell decreases the activity of HMGCoA reductase and other enzymes required for the biosynthesis of cholesterol, and the expression of LDL receptors. LDL receptors in the liver play a major role in determining plasma LDL levels (a low number of receptors is associated with high plasma LDL levels while a high number of hepatic LDL receptors is associated with low plasma LDL levels). The number of LDL receptors is regulated by the cholesterol content of the cell (35). When cellular cholesterol levels are decreased the transcription factor SREBP is transported from the endoplasmic reticulum to the Golgi where proteases cleave and activate SREBP, which then migrates to the nucleus and stimulates the expression of LDL receptors (Figure 4). Conversely, when cellular cholesterol levels are high SREBP remains in the endoplasmic reticulum in an inactive form and the expression of LDL receptors is low. As discussed later PCSK9 regulates the rate of degradation of LDL receptors.

Figure 3. LDL Receptor Pathway (figure modified from Annual Review of Biochemistry 46: 897, 1977)

Figure 4. SREBP Pathway (figure modified from Journal of Lipid Research 50: Supp S15, 2009)

LDL Receptor Related Protein 1 (LRP-1) (36)

LRP-1 is a member of the LDL receptor family. It is expressed in multiple tissues including the liver. LRP-1 recognizes Apo E and mediates the uptake of chylomicron remnants and IDL (VLDL remnants).

VLDL Receptor (37)

The VLDL receptor is a member of the LDL receptor family. The VLDLR is expressed in the heart, skeletal muscle, adipose tissue, endothelium, brain, macrophages, and other tissues. Interestingly it is not usually expressed in the liver but hepatic expression can be induced by endoplasmic reticulum stress and PPAR alpha activation. Apo E but not Apo B bind to the VLDL receptor thereby allowing for the uptake of triglyceride rich lipoprotein particles (VLDL and chylomicrons).

Class B Scavenger Receptor B1 (SR-B1) (38)

SR-B1 is expressed in the liver, adrenal glands, ovaries, testes, macrophages, and other cells. In the liver and steroid producing cells, it mediates the selective uptake of cholesterol esters from HDL particles. In macrophages and other cells, it facilitates the efflux of cholesterol from the cell to HDL particles.

ATP-Binding Cassette Transporter A1 (ABCA1) (39)

ABCA1 is expressed in many cells including hepatocytes, enterocytes, and macrophages. It mediates the transport of cholesterol and phospholipids from the cell to lipid poor HDL particles (pre-beta-HDL).

ATP-Binding Cassette Transporter G1 (ABCG1) (40)

ABCG1 is expressed in many different cell types and mediates the efflux of cholesterol from the cell to HDL particles.

ATP-Binding Cassette Transporter G5 and G8 (ABCG5/ABCG8) (41,42)

ABCG5 and ABCG8 are expressed in the liver and intestine and form a heterodimer. In the intestine, these transporters mediate the movement of plant sterols and cholesterol from inside the enterocyte into the intestinal lumen thereby decreasing the absorption of cholesterol and limiting the uptake of dietary plant sterols. In the liver, these transporters play a role in the movement of cholesterol and plant sterols into the bile facilitating the excretion of sterols.

Niemann-Pick C1-Like 1 (NPC1L1) (41)

NPC1L1 is expressed in the intestine and mediates the uptake of cholesterol and plant sterols from the intestinal lumen into the enterocyte. NPC1L1 is also expressed in the liver where it mediates the movement of cholesterol from hepatocytes into the bile.

ENZYMES AND TRANSFER PROTEINS INVOLVED IN LIPOPROTEIN METABOLISM

There are several enzymes and transfer proteins that play a key role in lipoprotein metabolism.

Lipoprotein Lipase (LPL) (43)

LPL is synthesized in muscle, heart, and adipose tissue, then secreted and attached to the endothelium of the adjacent blood capillaries. This enzyme hydrolyzes the triglycerides carried in chylomicrons and VLDL to fatty acids, which can be taken up by cells. The catabolism of triglycerides results in the conversion of chylomicrons into chylomicron remnants and VLDL into IDL (VLDL remnants). This enzyme requires Apo C-II as a cofactor. Apo A-V also plays a key role in the activation of this enzyme. In contrast Apo C-III and Apo A-II inhibit the activity of LPL. Insulin stimulates LPL expression and LPL activity is reduced in patients with poorly controlled diabetes, which can impair the metabolism of triglyceride rich lipoproteins leading to hypertriglyceridemia (44).

Hepatic Lipase (45)

Hepatic lipase is localized to the sinusoidal surface of liver cells. It mediates the hydrolysis of triglycerides and phospholipids in IDL and LDL leading to smaller particles (IDL is converted to LDL; LDL is converted from large LDL to small LDL). It also mediates the hydrolysis of triglycerides and phospholipids in HDL resulting in smaller HDL particles.

Endothelial Lipase (46)

Endothelial lipase plays a major role in hydrolyzing the phospholipids in HDL.

Lecithin: Cholesterol Acyltransferase (LCAT) (47)

LCAT is made in the liver. In the plasma, it catalyzes the synthesis of cholesterol esters in HDL by facilitating the transfer of a fatty acid from position 2 of lecithin to cholesterol. This allows for the transfer of the cholesterol from the surface of the HDL particle (free cholesterol) to the core of the HDL particle (cholesterol ester), which facilitates the continued uptake of free cholesterol by HDL particles by reducing the concentration of cholesterol on the surface of HDL.

Cholesteryl Ester Transfer Protein (CETP) (48,49)

This protein is synthesized in the liver and in the plasma mediates the transfer of cholesterol esters from HDL to VLDL, chylomicrons, and LDL and the transfer of triglycerides from VLDL and chylomicrons to HDL. Inhibition of CETP activity leads to an increase in HDL cholesterol and a decrease in LDL cholesterol.

Microsomal Triglyceride Transfer Protein (MTTP) (50)

MTTP is expressed primarily in the liver and small intestine and plays a crucial role in the synthesis of lipoproteins in these tissues. MTTP mediates the transfer of triglycerides to apolipoprotein B-100 in the liver to form VLDL and to apolipoprotein B-48 in the intestine to form chylomicrons.

EXOGENOUS LIPOPROTEIN PATHWAY (CHYLOMICRONS)

Figure 5. Exogenous Lipoprotein Pathway

Fat Absorption (51-54)

The exogenous lipoprotein pathway starts in the intestine. Dietary triglycerides (approximately 100 grams per day) are hydrolyzed to free fatty acids and monoacylglycerol by intestinal lipases and emulsified with bile acids, cholesterol, plant sterols, and fat-soluble vitamins to form micelles. While the fatty acids in the intestine are overwhelmingly accounted for by dietary intake the cholesterol in the intestinal lumen is primarily derived from bile (approximately 800-1200mg of cholesterol from bile vs. 200-500mg from diet). Plant sterols account for approximately 25% of dietary sterol intake (approximately 100-150mg/day). The cholesterol, plant sterols, fatty acids, monoacylglycerol, and fat-soluble vitamins contained in the micelles are then transported into the intestinal cells. The uptake of cholesterol and plant sterols from the intestinal lumen into intestinal cells is facilitated by a sterol transporter, Niemann-Pick C1- like 1 protein (NPC1L1) (Figure 6). Ezetimibe, a drug which inhibits intestinal cholesterol and plant sterol uptake, binds to NPC1L1 and inhibits its activity. Once in the intestinal cell the cholesterol and plant sterols may be transported back into the intestinal lumen, a process mediated by ABCG5 and ABCG8, or converted to sterol esters by acyl-CoA cholesterol acyl transferase (ACAT), which attaches a fatty acid to the sterol. Compared to cholesterol, plant sterols are poor substrates for ACAT and therefore the formation of plant sterol esters does not occur as efficiently as the formation of cholesterol esters. In humans, <5% of dietary plant sterols are absorbed and the vast majority are transported out of the intestine cell, a process mediated by ABCG5 and ABCG8, which are very efficient at effluxing plant sterols from the intestinal cell into the intestinal lumen. Patients with sitosterolemia have mutations in either ABCG5 or ABCG8 and net absorption of dietary plant sterols is increased (20-30% absorbed vs. < 5% in normal subjects) (55). Thus, ABCG5 and ABCG8 along with ACAT serve as gate keepers and block the uptake of plant sterols and likely also play an important role in determining the efficiency of cholesterol absorption (humans typically absorb only approximately 50% of dietary cholesterol with a range of 25-75%).

Figure 6. Intestinal Cell and Sterol Metabolism. C= cholesterol, CE= cholesterol ester.

The pathway of absorption of free fatty acids is not well understood but it is likely that both passive diffusion and specific transporters play a role. The fatty acid transporter CD36 is strongly expressed in the proximal third of the intestine and is localized to the villi. While this transporter likely plays a role in fatty acid uptake by intestinal cells, this transporter is not essential as humans and mice deficient in this protein do not have fat malabsorption. However, in mice deficient in CD36 there is a shift in the absorption of lipid to the distal intestine, suggesting pathways that can compensate for the absence of CD36. Fatty acid transport protein 4 (FATP4) is also highly expressed in the intestine. However, mice deficient in FATP4 do not have abnormalities in fat absorption. It is likely that there are multiple pathways for the absorption of fatty acids into intestinal cells. The pathways by which monoacylglycerols are absorbed by intestinal cells remain to be defined.

Formation of Chylomicrons (51,54)

The absorbed fatty acids and monoacylglycerols are utilized to synthesize triglycerides. The key enzymes required for triglyceride synthesis are monoacylglycerol acyltransferase (MGAT) and diacylglycerol transferase (DGAT). MGAT catalyzes the addition of a fatty acid to monoacylglycerol while DGAT catalyzes the addition of a fatty acid to diacylglycerol resulting in triglyceride formation.  As noted above, the majority of the cholesterol absorbed by the intestine is esterified to cholesterol esters by ACAT. The triglycerides and cholesterol esters are packaged into chylomicrons in the endoplasmic reticulum. The size and composition of the chylomicrons formed in the intestine are dependent on the amount of fat ingested and absorbed by the intestine and the type of fat absorbed. Increased fat absorption results in larger chylomicrons. The formation of chylomicrons in the endoplasmic reticulum requires the synthesis of Apo B-48 by the intestinal cell (Figure 6).  Microsomal triglyceride transfer protein (MTTP) is required for the movement of lipid from the endoplasmic reticulum to the Apo B-48. The absence of MTTP results in the inability to form chylomicrons (Abetalipoproteinemia) (56). Lomitapide inhibits MTTP function and is used to treat patients with homozygous Familial Hypercholesterolemia (57).

Chylomicron Metabolism (26,31,43,58-62)

Chylomicrons are secreted into the lymph and delivered via the thoracic duct to the circulation. It should be noted that this results in the newly formed chylomicrons being delivered to the systemic circulation and not delivered directly to the liver via the portal circulation. This facilitates the delivery of the nutrients contained in the chylomicrons to muscle and adipose tissue. In muscle and adipose tissue lipoprotein lipase (LPL) is expressed at high levels. LPL is synthesized in muscle and adipocytes and transported to the luminal surface of capillaries. Lipase maturation factor 1 plays a key role in the stabilization and movement of LPL from muscle cells and adipocytes to the capillary endothelial cell surface. Glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1 (GPIHBP1) binds LPL and transports it to the capillary lumen and anchors LPL to the capillary endothelium. Activation of LPL by Apo C-II, carried on the chylomicrons, leads to the hydrolysis of the triglycerides that are carried in the chylomicrons resulting in the formation of free fatty acids, which can be taken up by the adjacent muscle cells and adipocytes for either energy production or storage.  Fatty acid transport proteins (FATPs) and CD36 facilitate the uptake of fatty acids into adipocytes and muscle cells. Some of the free fatty acids released from chylomicrons bind to albumin and can be transported to other tissues. Apo A-V also plays an important role in activating LPL activity. Loss of function mutations in LPL, Apo C-II, GPIHPB1, lipase maturation factor 1, and Apo A-V can result in marked hypertriglyceridemia (familial chylomicronemia syndrome) (30). In addition, there are proteins that inhibit LPL activity. Apo C-III inhibits LPL activity and loss of function mutations in this gene are associated with increases in LPL activity and decreases in plasma triglyceride levels. Similarly, angiopoietin like protein 3 and 4, which target LPL for inactivation, regulate LPL activity. Loss of function mutations in these proteins also are associated with decreases in plasma triglyceride levels. Finally, the expression of LPL by muscle cells and adipocytes is regulated by hormones (particularly insulin), nutritional status, and inflammation.

The metabolism of the triglycerides carried in the chylomicrons results in a marked decrease in the size of these particles leading to the formation of chylomicron remnants, which are enriched in cholesterol esters and acquire Apo E. As these particles decrease in size phospholipids and apolipoproteins (Apo A and C) on the surface of the chylomicrons are transferred to other lipoproteins, mainly HDL. The transfer of Apo C-II from chylomicrons to HDL decreases the ability of LPL to further breakdown triglycerides. These chylomicron remnants are cleared from the circulation by the liver. The Apo E on the chylomicron remnants binds to the LDL receptor and other hepatic receptors such as LRP and syndecan-4 and the entire particle is taken up by the hepatocytes. Apo E is crucial for this process and mutations in Apo E (for example homozygosity for the Apo E2 isoform) can result in decreased chylomicron clearance and elevations in plasma cholesterol and triglyceride levels (familial dysbetalipoproteinemia) (30).

The exogenous lipoprotein pathway results in the efficient transfer of dietary fatty acids to muscle and adipose tissue for energy utilization and storage. The cholesterol is delivered to the liver where it can be utilized for the formation of VLDL, bile acids, or secreted back to the intestine via secretion into the bile. In normal individuals, this pathway can handle large amounts of fat (100 grams or more per day) without resulting in marked increases in plasma triglyceride levels. In fact, in a normal individual, a meal containing 75 grams of fat results in only a very modest increase in postprandial triglyceride levels. 

ENDOGENOUS LIPOPROTEIN PATHWAY (VLDL AND LDL)

Figure 7. Endogenous Lipoprotein Pathway

Formation of VLDL (50,63,64) 

In the liver triglycerides and cholesterol esters are transferred in the endoplasmic reticulum to newly synthesized Apo B-100. Similar to the intestine this transfer is mediated by MTTP. The availability of triglycerides is the primary determinant of the rate of VLDL synthesis. If the supply of triglyceride is limited the newly synthesized Apo B is rapidly degraded. Thus, in contrast to many proteins the rate of synthesis of the Apo B-100 is not the major determinant of the rate of secretion. Rather the amount of lipid available determines whether Apo B-100 is degraded or secreted. MTTP is required for the early addition of lipid to Apo B-100 particles but additional lipid is added via pathways that do not require MTTP. Additionally, the size of the VLDL particles is determined by the availability of triglycerides. When triglycerides are abundant the VLDL particles are large.

The quantity of fatty acids available for the synthesis of triglycerides is the main determinant of   triglyceride synthesis in the liver. The major sources of fatty acids are a) de novo fatty acid synthesis, b) the hepatic uptake of triglyceride rich lipoproteins, and c) the flux of fatty acids from adipose tissue to the liver. Diabetes, obesity, and the metabolic syndrome are common causes of an increase in hepatic triglyceride levels and the increased secretion of VLDL (44,65).

Loss of function mutations in either Apo B-100 or MTTP result in the failure to produce VLDL and marked decreases in plasma triglyceride and cholesterol levels (familial hypobetalipoproteinemia or abetalipoproteinemia) (56). The precise pathway by which the newly synthesized VLDL particles are secreted from the hepatocyte into the circulation is not resolved.

VLDL Metabolism (6,58)

VLDL particles are transported to peripheral tissues where the triglycerides are hydrolyzed by LPL and fatty acids are released. This process is very similar to that described above for chylomicrons and there is competition between the metabolism of chylomicrons and VLDL. High levels of chylomicrons can inhibit the clearance of VLDL. The removal of triglycerides from VLDL results in the formation of VLDL remnants (Intermediate density lipoproteins (IDL)). These IDL particles are relatively enriched in cholesterol esters and acquire Apo E from HDL particles. In a pathway analogous to the removal of chylomicron remnants these IDL particles can be removed from the circulation by the liver via binding of Apo E to LDL and LRP receptors. However, while the vast majority of chylomicron remnants are rapidly cleared from the circulation by the liver, only a fraction of IDL particles are cleared (approximately 50% but varies). The remaining triglycerides in the IDL particles are hydrolyzed by hepatic lipase leading to a further decrease in triglyceride content and the exchangeable apolipoproteins are transferred from the IDL particles to other lipoproteins leading to the formation of LDL. These LDL particles predominantly contain cholesterol esters and Apo B-100.  Thus, LDL is a product of VLDL metabolism.

LDL Metabolism (34,66-69)

The levels of plasma LDL are determined by the rate of LDL production and the rate of LDL clearance, both of which are regulated by the number of LDL receptors in the liver. The production rate of LDL from VLDL is partially determined by hepatic LDL receptor activity with a high LDL receptor activity resulting in a decrease in LDL production due to an increase in IDL uptake. Conversely, low LDL receptor activity results in an increase in LDL production formation due to a decrease in IDL uptake. With regards to LDL clearance, approximately 70% of circulating LDL is cleared via hepatocyte LDL receptor mediated endocytosis with the remainder taken up by extrahepatic tissues. An increase in the number of hepatic LDL receptors therefore increases LDL clearance leading to a decrease in plasma LDL levels. Conversely, a decrease in hepatic LDL receptors slows LDL clearance leading to an increase in plasma LDL levels. Thus, the level of hepatic LDL receptors plays a key role in regulating plasma LDL levels. Many of the drugs used to lower plasma LDL levels, such as the statins, ezetimibe, PCSK9 inhibitors, bile acid sequestrants and bempedoic acid lower plasma LDL levels by increasing the number of hepatic LDL receptors (57).

The levels of LDL receptors in the liver are mainly regulated by the cholesterol content of the hepatocyte. As cholesterol levels in the cell decrease, inactive sterol regulatory element binding proteins (SREBPs), which are transcription factors that mediate the expression of LDL receptors and key genes involved in cholesterol and fatty acid metabolism, are transported from the endoplasmic reticulum to the Golgi where proteases cleave the SREBPs into active transcription factors (Figure 4). These active SREBPs move to the nucleus where they stimulate the transcription of the LDL receptor and enzymes required for cholesterol synthesis, including HMG-CoA reductase, the rate limiting enzyme in cholesterol synthesis. If cholesterol levels in the cell are high, then the SREBPs remain in the endoplasmic reticulum in an inactive form and do not stimulate LDL receptor synthesis. In addition, cholesterol in the cell is oxidized and oxidized sterols activate LXR, a nuclear hormone receptor that is a transcription factor, which stimulates the transcription of E3 ubiquitin ligase that mediates the ubiquitination and degradation of the low-density lipoprotein receptor (Inducible degrader of the low-density lipoprotein receptor (IDOL)). Thus, the cell can sense the availability of cholesterol and regulate LDL receptor activity. If the cholesterol content of the cell is decreased LDL receptor activity is increased to allow for the increased uptake of cholesterol. Conversely, if the cholesterol content of the cell is increased LDL receptor activity is decreased and the uptake of LDL by the cell is diminished. Statins, ezetimibe, bile acid sequestrants, and bempedoic acid decrease hepatic cholesterol levels thereby increasing LDL receptor levels and decreasing plasma LDL levels (57). Finally, the LDL receptor is targeted for degradation by PCSK9, a secreted protein that binds to the LDL receptor and enhances LDL receptor degradation in the lysosomes. Loss of function mutations in PCSK9 and drugs that inhibit PCSK9 result in increased LDL receptor activity and decreased LDL levels while gain of function mutations in PCSK9 lead to decreased LDL receptor activity and elevations in LDL levels.

Thus, the endogenous lipoprotein pathway facilitates the movement of triglycerides synthesized in the liver to muscle and adipose tissue. Additionally, it also provides a pathway for the transport of cholesterol from the liver to peripheral tissues.

HDL METABOLISM AND REVERSE CHOLESTEROL TRANSPORT (38-40,47,48,70,71)

Figure 8. HDL Metabolism

HDL Formation

Several steps are required to generate mature HDL particles. The first step involves the synthesis of the main structural protein contained in HDL, Apo A-I. Apo A-I is synthesized predominantly by the liver and intestine. After Apo A-I is secreted, it acquires cholesterol and phospholipids that are effluxed from hepatocytes and enterocytes. The efflux of cholesterol and phospholipids to the newly synthesized lipid poor Apo A-I (pre-beta HDL) is facilitated by ABCA1. Patients with loss of function mutations in ABCA1 (Tangiers disease) fail to lipidate the newly secreted Apo A-I leading to the rapid catabolism of Apo A-I and very low HDL levels (72). Using mice with targeted knock-out of ABCA1 it has been shown that HDL cholesterol levels are reduced by 80% in mice lacking ABCA1 in the liver and 30% in mice lacking ABCA1 in the intestine. While initially cholesterol and phospholipids are obtained from the liver and intestine, HDL also acquires lipid from other tissues and from other lipoproteins. Muscle cells, adipocytes, and other tissues express ABCA1 and ABCG1 and are able to transfer cholesterol and phospholipids to Apo A-I particles. Additionally, as noted above, newly formed HDL can also obtain cholesterol and phospholipids from chylomicrons and VLDL during their lipolysis by LPL. This accounts for the observation that patients with high plasma triglyceride levels due to decreased clearance frequently have low HDL cholesterol levels. Additionally, phospholipid transfer protein (PLTP) facilitates the movement of phospholipids between lipoproteins; mice lacking PLTP have a marked reduction in HDL cholesterol and Apo A-I levels. Finally, the lipolysis of triglyceride rich lipoproteins also results in the transfer of apolipoproteins from these particles to HDL.

HDL Cholesterol Esterification

As noted earlier the cholesterol in the core of HDL is esterified (cholesterol esters). The cholesterol that is effluxed from cells to HDL is free cholesterol and is localized on the surface of HDL particles. In order to form mature large spherical HDL particles with a core of cholesterol esters the free cholesterol transferred from cells to the surface of HDL particles must be esterified. LCAT, an HDL associated enzyme catalyzes the transfer of a fatty acid from phospholipids to free cholesterol resulting in the formation of cholesterol esters. The cholesterol ester formed is then able to move from the surface of the HDL particle to the core allowing additional free cholesterol to be transferred from cells to HDL particles. Apo A-I is an activator of LCAT and facilitates this esterification process. LCAT activity is required for the formation of large HDL particles. LCAT deficiency in humans results in decreased HDL cholesterol and Apo A-I levels and a higher percentage of small HDL particles (72).

HDL Metabolism

Lipases and transfer proteins play an important role in determining the size and composition of HDL particles. The cholesterol ester carried in the core of HDL particles may be transferred to Apo B containing particles in exchange for triglyceride. This transfer is mediated by CETP and results in HDL enriched in triglycerides which may then be metabolized by lipases. Humans deficient in CETP activity have very high HDL cholesterol levels and large HDL particles (72). CETP also impacts LDL cholesterol levels and the absence of CETP results in a decrease in LDL cholesterol. Mice do not have CETP and have relatively high HDL cholesterol levels and low LDL cholesterol levels. Hepatic lipase hydrolyzes both triglycerides and phospholipids in HDL. The triglycerides that are transferred to HDL by CETP activity are catabolized by hepatic lipase resulting in the formation of small HDL particles and Apo A-I more easily disassociates from small HDL resulting in the release of Apo A-I and increased Apo A-I degradation. Genetic deficiency of hepatic lipase results in a modest elevation in HDL cholesterol levels and larger HDL particles (72). Hepatic lipase activity is increased in insulin resistant states and this is associated with reduced HDL cholesterol levels. Endothelial cell lipase is a phospholipase that hydrolyzes the phospholipids carried in HDL particles. In mice increased endothelial lipase activity results in decreased HDL cholesterol levels while decreased endothelial lipase activity increases HDL cholesterol levels.

The cholesterol carried on HDL is primarily delivered to the liver. The uptake of HDL cholesterol by the liver is mediated by SR-BI, which promotes the selective uptake of HDL cholesterol. The HDL particle binds to SR-BI and the cholesterol in HDL is transported into the liver without internalization of the HDL particle. A smaller cholesterol depleted HDL particle is formed, which is then released back into the circulation. In SR-BI deficient mice there is a marked increase in HDL cholesterol levels. Interestingly the risk of atherosclerosis is increased in these SR-BI deficient mice despite an increase in HDL cholesterol levels. Notably, while HDL cholesterol levels are increased in SR-B1 deficient mice the reverse cholesterol transport pathway is actually reduced. While in mice the physiological importance of the hepatic SR-BI pathway is clear, the role in humans is uncertain. In mice, the movement of cholesterol from peripheral tissues to the liver is dependent solely on SR-BI while in humans CETP can facilitate the transport of cholesterol from HDL to Apo B containing lipoproteins, which serves as an alternative pathway for the transport cholesterol to the liver. 

Apo A-I is metabolized independently of HDL cholesterol. Most of the Apo A-I is catabolized by the kidneys with the remainder catabolized by the liver. Lipid free or lipid poor Apo A-I is filtered by the kidneys and then taken up by the renal tubules. The size of the Apo A-I particle determines whether it can be filtered by the kidneys and hence the degree of lipidation of Apo A-I determines the rate of catabolism. Conditions or disease states (for example Tangiers disease, which is due to a mutation in ABCA1, or LCAT deficiency) that result in lipid poor HDL led to the accelerated catabolism of Apo A-I by the kidney. Apo A-I binds to cubilin, which in conjunction with megalin, a member of the LDL receptor gene family, leads to the uptake and degradation of filtered Apo A-I by renal tubular cells. While the liver is also involved in the catabolism of Apo A-I, the mechanisms are poorly understood. HDL particles may contain Apo E and it is therefore possible that Apo E containing HDL particles are taken up via the LDL receptor and other Apo E receptors in the liver and degraded.

Reverse Cholesterol Transport (73-78)

Peripheral cells accumulate cholesterol through the uptake of circulating lipoproteins and de novo cholesterol synthesis. Most cells do not have a mechanism for catabolizing cholesterol. Cells that synthesize steroid hormones can convert cholesterol to glucocorticoids, estrogen, testosterone, etc. Intestinal cells, sebocytes, and keratinocytes can secrete cholesterol into the intestinal lumen or onto the skin surface thereby eliminating cholesterol. However, in order for most cells to decrease their cholesterol content reverse cholesterol transport is required. From a clinical point of view, the ability of macrophages in the arterial wall to efficiently efflux cholesterol into the reverse cholesterol transport pathway may play an important role in the prevention of atherosclerosis.

As noted earlier ABCA1 plays an important role in the efflux of cholesterol to lipid poor pre-beta Apo A-I particles (Figure 9). ABCG1 plays an important role in the efflux of cholesterol from cells to mature HDL particles. In some studies, SR-B1 also plays a role in the efflux of cholesterol to mature HDL particles. Additionally, passive diffusion of cholesterol from the plasma membrane to HDL may also contribute to cholesterol efflux. The levels of both ABCA1 and ABCG1 are increased by LXR activation. LXR is a nuclear hormone transcription factor that is activated by oxysterols. As the cholesterol levels in a cell increase the formation of oxysterols increases leading to the activation of LXR resulting in an increase in ABCA1 and ABCG1 expression, which will result in the enhanced efflux of cholesterol from the cell to HDL.  Additionally, ABCA1 and ABCG1 mRNAs are targeted for degradation by miR-33, a microRNA that is embedded within the SREBP2 gene. An increase in cellular cholesterol decreases the expression of SREBP2 leading to a decrease in miR-33 resulting in enhanced LXR expression. Thus, the decrease in SREBP2 transcription will lead to a decrease in LDL receptor activity and a reduction in cholesterol uptake, while simultaneously, a decrease in miR-33 will lead to an increase in LXR activity stimulating the expression of ABCA1 and ABCG1 resulting in increased cholesterol efflux. Conversely a decrease in cellular cholesterol levels will increase SREBP2 expression resulting in an increase in LDL receptor activity and an increase in miR-33, which will result in a decrease in LXR activity, decreased expression of ABCA1 and ABCG1, and a reduction in cholesterol efflux. Together changes in cholesterol uptake mediated by the LDL receptor and cholesterol efflux mediated by ABCA1 and ABCG1 will maintain cellular cholesterol homeostasis.

Figure 9. Cholesterol Efflux from Macrophages (modified from J. Clinical Investigation 116: 3090, 2006)

Once cholesterol is transferred from cells to HDL there are two pathways for the cholesterol to be transported and taken up by the liver. As discussed earlier, HDL can interact with hepatic SR-BI receptors resulting in the selective uptake of cholesterol from HDL particles. Alternatively, CETP can transfer cholesterol from HDL particles to Apo B containing particles with the subsequent uptake of Apo B containing lipoproteins by the liver. After the delivery of cholesterol to the liver there are several pathways by which the cholesterol can be eliminated. Cholesterol can be converted to bile acids and secreted in the bile. Alternatively, cholesterol can be directly secreted into the bile. ABCG5 and ABCG8 promote the transport of cholesterol into the bile and the expression of these genes is enhanced by LXR activation. Thus, an increase in hepatic cholesterol levels leading to increased oxysterol production will activate LXR resulting in the increased expression of ABCG5 and ABCG8 facilitating the secretion of cholesterol in the bile.

Evidence suggests that reverse cholesterol transport plays an important role in protecting from the development of atherosclerosis. It should be noted that HDL cholesterol levels may not be indicative of the rate of reverse cholesterol transport. As described above reverse cholesterol transport involves several steps and the level of HDL cholesterol may not accurately reflect these steps. For example, studies have shown that the ability of HDL to promote cholesterol efflux from macrophages can vary. Thus, the same level of HDL cholesterol may not have equivalent abilities to mediate the initial step of reverse cholesterol transport.  

LIPOPROTEIN (a) (14-16,79)

Figure 10. Lp (a)

Lp (a) consists of an LDL molecule and a unique apolipoprotein (a), which is attached to the Apo B-100 of the LDL via a single disulfide bound. Lp (a) contain Apo (a) and Apo B-100 in a 1:1 molar ratio. Like Apo B-100, apo (a) is also made by hepatocytes. Apo (a) contains multiple kringle motifs that are similar to the kringle repeats in plasminogen. The number of kringle repeats can vary and thus the molecular weight of apo (a) can range from 250,000 to 800,000.  The levels of Lp (a) in plasma can vary more than a 1000-fold ranging from undetectable to greater than 100mg/dl. Lp (a) levels largely reflect Lp (a) production rates, which are primarily genetically regulated and not greatly affected by environmental factors. Individuals with high molecular weight Apo (a) proteins tend to have lower levels of Lp (a) while individuals with low molecular weight Apo (a) tend to have higher levels. It is hypothesized that the liver is less efficient in secreting high molecular weight Apo (a). The mechanism of Lp (a) clearance is uncertain but does not appear to primarily involve LDL receptors. Therapies that accelerate LDL clearance and lower LDL levels do not lower Lp (a) levels (for example statin therapy). The kidney appears to play an important role in Lp (a) clearance as kidney disease is associated with delayed clearance and elevations in Lp (a) levels.

 Elevated plasma Lp(a) levels are associated with an increased risk of atherosclerosis. Apo (a) is an inhibitor of fibrinolysis and enhances the uptake of lipoproteins by macrophages, both of which could account for the increased the risk of atherosclerosis in individuals with elevated Apo (a) levels. Additionally, Lp (a) is the major lipoprotein carrier of oxidized phospholipids, which are inflammatory and could also increase the risk of atherosclerosis. The physiologic function of Apo (a) is unknown. Apo (a) is found in primates but not in other species.

ACKNOWLEDGEMENTS

This work was supported by grants from the Northern California Institute for Research and Education.

REFERENCES

1. Feingold KR, Grunfeld C. Lipids: a key player in the battle between the host and microorganisms. J Lipid Res 2012; 53:2487-2489
2. Nielsen LB, Nielsen MJ, Moestrup SK. Lipid metabolism: an apolipoprotein-derived weapon combating trypanosoma infection. Curr Opin Lipidol 2006; 17:699-701
3. Feingold KR. The bidirectional link between HDL and COVID-19 infections. J Lipid Res 2021; 62:100067
4. Smith LC, Pownall HJ, Gotto AM, Jr. The plasma lipoproteins: structure and metabolism. Annu Rev Biochem 1978; 47:751-757
5. Julve J, Martin-Campos JM, Escola-Gil JC, Blanco-Vaca F. Chylomicrons: Advances in biology, pathology, laboratory testing, and therapeutics. Clin Chim Acta 2016; 455:134-148
6. Chait A, Ginsberg HN, Vaisar T, Heinecke JW, Goldberg IJ, Bornfeldt KE. Remnants of the Triglyceride-Rich Lipoproteins, Diabetes, and Cardiovascular Disease. Diabetes 2020; 69:508-516
7. Krauss RM, King SM. Remnant lipoprotein particles and cardiovascular disease risk. Best Pract Res Clin Endocrinol Metab 2023; 37:101682
8. Berneis KK, Krauss RM. Metabolic origins and clinical significance of LDL heterogeneity. J Lipid Res 2002; 43:1363-1379
9. Asztalos BF, Niisuke K, Horvath KV. High-density lipoprotein: our elusive friend. Curr Opin Lipidol 2019; 30:314-319
10. Thakkar H, Vincent V, Sen A, Singh A, Roy A. Changing Perspectives on HDL: From Simple Quantity Measurements to Functional Quality Assessment. J Lipids 2021; 2021:5585521
11. Thomas SR, Zhang Y, Rye KA. The pleiotropic effects of high-density lipoproteins and apolipoprotein A-I. Best Pract Res Clin Endocrinol Metab 2023; 37:101689
12. Vaisar T, Pennathur S, Green PS, Gharib SA, Hoofnagle AN, Cheung MC, Byun J, Vuletic S, Kassim S, Singh P, Chea H, Knopp RH, Brunzell J, Geary R, Chait A, Zhao XQ, Elkon K, Marcovina S, Ridker P, Oram JF, Heinecke JW. Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL. J Clin Invest 2007; 117:746-756
13. Kostner KM, Kostner GM. Lipoprotein (a): a historical appraisal. J Lipid Res 2017; 58:1-14
14. Nordestgaard BG, Langsted A. Lipoprotein (a) as a cause of cardiovascular disease: insights from epidemiology, genetics, and biology. J Lipid Res 2016; 57:1953-1975
15. Schmidt K, Noureen A, Kronenberg F, Utermann G. Structure, function, and genetics of lipoprotein (a). J Lipid Res 2016; 57:1339-1359
16. Khovidhunkit W. Lipoprotein(a). In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrere B, Levy M, McGee EA, McLachlan R, New M, Purnell J, Sahay R, Shah AS, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, eds. Endotext. South Dartmouth (MA) 2023.
17. Mahley RW, Innerarity TL, Rall SC, Jr., Weisgraber KH. Plasma lipoproteins: apolipoprotein structure and function. J Lipid Res 1984; 25:1277-1294
18. Breslow JL. Human apolipoprotein molecular biology and genetic variation. Annu Rev Biochem 1985; 54:699-727
19. Frank PG, Marcel YL. Apolipoprotein A-I: structure-function relationships. J Lipid Res 2000; 41:853-872
20. Chan DC, Ng TW, Watts GF. Apolipoprotein A-II: evaluating its significance in dyslipidaemia, insulin resistance, and atherosclerosis. Ann Med 2012; 44:313-324
21. Wang F, Kohan AB, Lo CM, Liu M, Howles P, Tso P. Apolipoprotein A-IV: a protein intimately involved in metabolism. J Lipid Res 2015; 56:1403-1418
22. Hubacek JA. Apolipoprotein A5 fifteen years anniversary: Lessons from genetic epidemiology. Gene 2016; 592:193-199
23. Sharma V, Forte TM, Ryan RO. Influence of apolipoprotein A-V on the metabolic fate of triacylglycerol. Curr Opin Lipidol 2013; 24:153-159
24. Anant S, Davidson NO. Molecular mechanisms of apolipoprotein B mRNA editing. Curr Opin Lipidol 2001; 12:159-165
25. Levenson AE, de Ferranti SD. Familial Hypercholesterolemia. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrere B, Levy M, McGee EA, McLachlan R, New M, Purnell J, Sahay R, Shah AS, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, eds. Endotext. South Dartmouth (MA) 2023.
26. Wolska A, Dunbar RL, Freeman LA, Ueda M, Amar MJ, Sviridov DO, Remaley AT. Apolipoprotein C-II: New findings related to genetics, biochemistry, and role in triglyceride metabolism. Atherosclerosis 2017; 267:49-60
27. Ramms B, Gordts P. Apolipoprotein C-III in triglyceride-rich lipoprotein metabolism. Curr Opin Lipidol 2018; 29:171-179
28. D'Erasmo L, Di Costanzo A, Gallo A, Bruckert E, Arca M. ApoCIII: A multifaceted protein in cardiometabolic disease. Metabolism 2020; 113:154395
29. Wolska A, Reimund M, Remaley AT. Apolipoprotein C-II: the re-emergence of a forgotten factor. Curr Opin Lipidol 2020; 31:147-153
30. Patni N, Ahmad Z, Wilson DP. Genetics and Dyslipidemia. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrere B, Levy M, McGee EA, McLachlan R, New M, Purnell J, Sahay R, Shah AS, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, eds. Endotext. South Dartmouth (MA) 2023.
31. Taskinen MR, Boren J. Why Is Apolipoprotein CIII Emerging as a Novel Therapeutic Target to Reduce the Burden of Cardiovascular Disease? Curr Atheroscler Rep 2016; 18:59
32. Witztum JL, Gaudet D, Freedman SD, Alexander VJ, Digenio A, Williams KR, Yang Q, Hughes SG, Geary RS, Arca M, Stroes ESG, Bergeron J, Soran H, Civeira F, Hemphill L, Tsimikas S, Blom DJ, O'Dea L, Bruckert E. Volanesorsen and Triglyceride Levels in Familial Chylomicronemia Syndrome. N Engl J Med 2019; 381:531-542
33. Mahley RW. Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders. J Mol Med (Berl) 2016; 94:739-746
34. Goldstein JL, Brown MS. The LDL receptor. Arterioscler Thromb Vasc Biol 2009; 29:431-438
35. Goldstein JL, DeBose-Boyd RA, Brown MS. Protein sensors for membrane sterols. Cell 2006; 124:35-46
36. van de Sluis B, Wijers M, Herz J. News on the molecular regulation and function of hepatic low-density lipoprotein receptor and LDLR-related protein 1. Curr Opin Lipidol 2017; 28:241-247
37. Krauss RM, Lu JT, Higgins JJ, Clary CM, Tabibiazar R. VLDL receptor gene therapy for reducing atherogenic lipoproteins. Mol Metab 2023; 69:101685
38. Trigatti BL. SR-B1 and PDZK1: partners in HDL regulation. Curr Opin Lipidol 2017; 28:201-208
39. Wang S, Smith JD. ABCA1 and nascent HDL biogenesis. Biofactors 2014; 40:547-554
40. Baldan A, Tarr P, Lee R, Edwards PA. ATP-binding cassette transporter G1 and lipid homeostasis. Curr Opin Lipidol 2006; 17:227-232
41. Kidambi S, Patel SB. Cholesterol and non-cholesterol sterol transporters: ABCG5, ABCG8 and NPC1L1: a review. Xenobiotica 2008; 38:1119-1139
42. Patel SB, Graf GA, Temel RE. ABCG5 and ABCG8: more than a defense against xenosterols. J Lipid Res 2018; 59:1103-1113
43. Olivecrona G. Role of lipoprotein lipase in lipid metabolism. Curr Opin Lipidol 2016; 27:233-241
44. Feingold KR. Dyslipidemia in Patients with Diabetes. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrere B, Levy M, McGee EA, McLachlan R, New M, Purnell J, Sahay R, Shah AS, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, eds. Endotext. South Dartmouth (MA) 2023.
45. Kobayashi J, Miyashita K, Nakajima K, Mabuchi H. Hepatic Lipase: a Comprehensive View of its Role on Plasma Lipid and Lipoprotein Metabolism. J Atheroscler Thromb 2015; 22:1001-1011
46. Yasuda T, Ishida T, Rader DJ. Update on the role of endothelial lipase in high-density lipoprotein metabolism, reverse cholesterol transport, and atherosclerosis. Circ J 2010; 74:2263-2270
47. Ossoli A, Simonelli S, Vitali C, Franceschini G, Calabresi L. Role of LCAT in Atherosclerosis. J Atheroscler Thromb 2016; 23:119-127
48. Mabuchi H, Nohara A, Inazu A. Cholesteryl ester transfer protein (CETP) deficiency and CETP inhibitors. Mol Cells 2014; 37:777-784
49. Shrestha S, Wu BJ, Guiney L, Barter PJ, Rye KA. Cholesteryl ester transfer protein and its inhibitors. J Lipid Res 2018; 59:772-783
50. Hooper AJ, Burnett JR, Watts GF. Contemporary aspects of the biology and therapeutic regulation of the microsomal triglyceride transfer protein. Circ Res 2015; 116:193-205
51. Abumrad NA, Davidson NO. Role of the gut in lipid homeostasis. Physiol Rev 2012; 92:1061-1085
52. D'Aquila T, Hung YH, Carreiro A, Buhman KK. Recent discoveries on absorption of dietary fat: Presence, synthesis, and metabolism of cytoplasmic lipid droplets within enterocytes. Biochim Biophys Acta 2016; 1861:730-747
53. Hussain MM. Intestinal lipid absorption and lipoprotein formation. Curr Opin Lipidol 2014; 25:200-206
54. Kindel T, Lee DM, Tso P. The mechanism of the formation and secretion of chylomicrons. Atheroscler Suppl 2010; 11:11-16
55. Liebeskind A, Peterson AL, Wilson D. Sitosterolemia. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrere B, Levy M, McGee EA, McLachlan R, New M, Purnell J, Sahay R, Shah AS, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, eds. Endotext. South Dartmouth (MA) 2023.
56. Shapiro MD, Feingold KR. Monogenic Disorders Causing Hypobetalipoproteinemia. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrere B, Levy M, McGee EA, McLachlan R, New M, Purnell J, Sahay R, Shah AS, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, eds. Endotext. South Dartmouth (MA) 2021.
57. Feingold KR. Cholesterol Lowering Drugs. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrere B, Levy M, McGee EA, McLachlan R, New M, Purnell J, Sahay R, Shah AS, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, eds. Endotext. South Dartmouth (MA) 2021.
58. Dallinga-Thie GM, Franssen R, Mooij HL, Visser ME, Hassing HC, Peelman F, Kastelein JJ, Peterfy M, Nieuwdorp M. The metabolism of triglyceride-rich lipoproteins revisited: new players, new insight. Atherosclerosis 2010; 211:1-8
59. Dijk W, Kersten S. Regulation of lipid metabolism by angiopoietin-like proteins. Curr Opin Lipidol 2016; 27:249-256
60. Fong LG, Young SG, Beigneux AP, Bensadoun A, Oberer M, Jiang H, Ploug M. GPIHBP1 and Plasma Triglyceride Metabolism. Trends Endocrinol Metab 2016; 27:455-469
61. Peterfy M. Lipase maturation factor 1: a lipase chaperone involved in lipid metabolism. Biochim Biophys Acta 2012; 1821:790-794
62. Young SG, Fong LG, Beigneux AP, Allan CM, He C, Jiang H, Nakajima K, Meiyappan M, Birrane G, Ploug M. GPIHBP1 and Lipoprotein Lipase, Partners in Plasma Triglyceride Metabolism. Cell Metab 2019; 30:51-65
63. Tiwari S, Siddiqi SA. Intracellular trafficking and secretion of VLDL. Arterioscler Thromb Vasc Biol 2012; 32:1079-1086
64. Choi SH, Ginsberg HN. Increased very low density lipoprotein (VLDL) secretion, hepatic steatosis, and insulin resistance. Trends Endocrinol Metab 2011; 22:353-363
65. Feingold KR. Obesity and Dyslipidemia. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrere B, Levy M, McGee EA, McLachlan R, New M, Purnell J, Sahay R, Shah AS, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, eds. Endotext. South Dartmouth (MA) 2023.
66. Goldstein JL, Brown MS. A century of cholesterol and coronaries: from plaques to genes to statins. Cell 2015; 161:161-172
67. Horton JD, Cohen JC, Hobbs HH. Molecular biology of PCSK9: its role in LDL metabolism. Trends Biochem Sci 2007; 32:71-77
68. Zhang L, Reue K, Fong LG, Young SG, Tontonoz P. Feedback regulation of cholesterol uptake by the LXR-IDOL-LDLR axis. Arterioscler Thromb Vasc Biol 2012; 32:2541-2546
69. Brown MS, Radhakrishnan A, Goldstein JL. Retrospective on Cholesterol Homeostasis: The Central Role of Scap. Annual review of biochemistry 2017;
70. Rosenson RS, Brewer HB, Jr., Davidson WS, Fayad ZA, Fuster V, Goldstein J, Hellerstein M, Jiang XC, Phillips MC, Rader DJ, Remaley AT, Rothblat GH, Tall AR, Yvan-Charvet L. Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport. Circulation 2012; 125:1905-1919
71. Rye KA, Barter PJ. Cardioprotective functions of HDLs. J Lipid Res 2014; 55:168-179
72. Shapiro MD, Feingold KR. Monogenic Disorders Altering HDL Levels. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrere B, Levy M, McGee EA, McLachlan R, New M, Purnell J, Sahay R, Shah AS, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, eds. Endotext. South Dartmouth (MA) 2021.
73. Zhao Y, Van Berkel TJ, Van Eck M. Relative roles of various efflux pathways in net cholesterol efflux from macrophage foam cells in atherosclerotic lesions. Curr Opin Lipidol 2010; 21:441-453
74. Lee-Rueckert M, Escola-Gil JC, Kovanen PT. HDL functionality in reverse cholesterol transport--Challenges in translating data emerging from mouse models to human disease. Biochim Biophys Acta 2016; 1861:566-583
75. Tall AR. Cholesterol efflux pathways and other potential mechanisms involved in the athero-protective effect of high density lipoproteins. J Intern Med 2008; 263:256-273
76. Siddiqi HK, Kiss D, Rader D. HDL-cholesterol and cardiovascular disease: rethinking our approach. Curr Opin Cardiol 2015; 30:536-542
77. Moore KJ, Rayner KJ, Suarez Y, Fernandez-Hernando C. The role of microRNAs in cholesterol efflux and hepatic lipid metabolism. Annu Rev Nutr 2011; 31:49-63
78. Ouimet M, Barrett TJ, Fisher EA. HDL and Reverse Cholesterol Transport. Circ Res 2019; 124:1505-1518
79. Hoover-Plow J, Huang M. Lipoprotein(a) metabolism: potential sites for therapeutic targets. Metabolism 2013; 62:479-491

ABSTRACT

Monogenic mutations leading to hypobetalipoproteinemia are rare. The monogenic causes of hypobetalipoproteinemia include familial hypobetalipoproteinemia, abetalipoproteinemia, chylomicron retention disease, loss of function mutations in PCSK9, and loss of function mutations in angiopoietin-like protein 3 (ANGPTL3) (Familiar Combined Hypolipidemia). This chapter describes the etiology, pathogenesis, clinical and laboratory findings, and the treatment of these rare monogenic disorders.

INTRODUCTION

Monogenic mutations leading to hypobetalipoproteinemia are rare. The monogenic causes of hypobetalipoproteinemia include familial hypobetalipoproteinemia (FHBL), abetalipoproteinemia (ABL), chylomicron retention disease (CMRD), loss of function mutations in PCSK9, and loss of function mutations in angiopoietin-like protein 3 (ANGPTL3) (Familial Combined Hypolipidemia, FCH) (1). Increased understanding of the genetic and the molecular underpinnings of these disorders has allowed a focused prioritization of therapeutic targets for drug development. Table 1 summarizes genetic, lipid, and clinical features of the major hypobetalipoproteinemia syndromes and table 2 provides a new classification of these disorders. Of note the parental lipid profile is normal in abetalipoproteinemia and chylomicron retention disease.

It should be recognized that secondary, non-familial, forms of hypobetalipoproteinemia occur and include strict vegan diet, malnutrition, malabsorption, hyperthyroidism, malignancy, and chronic liver disease. In addition, hypobetalipoproteinemia can also be due to polymorphisms in multiple genes that together result in hypobetalipoproteinemia (polygenic etiology) (2-4). In a study of 111 patients with LDL-C levels below the fifth percentile 36% had monogenic hypobetalipoproteinemia, 34% had polygenic hypobetalipoproteinemia, and 30% had hypobetalipoproteinemia from an unknown cause (2). In a study of women with an LDL-C ≤1st percentile (≤50 mg/dL) 15.7% carried mutations causing monogenic hypocholesterolemia and 49.6% were genetically predisposed to a low LDL-C on the basis of an extremely low weighted polygenetic risk score (4). Of note individuals with monogenic hypobetalipoproteinemia are more likely to have liver steatosis than individuals without a monogenic disorder (2).

ACD- autosomal co-dominant; AR- autosomal recessive; FHBL- familial hypobetalipoproteinemia; ABL- abetalipoproteinemia; FCH- Familiar Combined Hypolipidemia; CMRD- chylomicron retention disease, MTTP- microsomal triglyceride transfer protein; ANGPTL3- angiopoietin-like protein 3; ASCVD- atherosclerotic cardiovascular disease.

Modified from (5).

FAMILIAL HYPOBETALIPOPROTEINEMIA  

Familial Hypobetalipoproteinemia (FHBL) is a relatively common autosomal semi-dominant disorder most commonly due to truncation mutations in the gene coding for Apo B (1,6-8). The prevalence of heterozygous FHBL is estimated to be 1 in 700 to 3000 (1). Variants that lead to truncated proteins that are 30% in length or shorter have more severe signs and symptoms than those with longer truncated proteins (6,7). The truncated forms of Apo B found in FHBL are generally non-functional (truncation decreases lipidation and secretion) and are catabolized quickly, resulting in markedly reduced levels in the plasma (Apo B <5th percentile and LDL-C typically between 20- 50 mg/dL) (7,8). Although there is one normal allele in heterozygous FHBL, plasma Apo B levels are approximately 25% of normal rather than the predicted 50% (8). These lower-than-expected levels result from a lower secretion rate of VLDL Apo B from the liver, decreased production of LDL Apo B, increased catabolism of VLDL, and extremely low secretion of the truncated Apo B (6-8). Given the reduced substrate (Apo B) for lipid (predominantly triglyceride) loading, fatty liver develops in these patients (6,9). Hepatic steatosis and mild elevation of liver enzymes are common in heterozygous FHBL (6,9). Interestingly, individuals with monogenic hypobetalipoproteinemia had a much greater prevalence of hepatic dysfunction than individuals with polygenic hypobetalipoproteinemia (2). In contrast to non-alcoholic fatty liver disease, FHBL is not associated with hepatic or peripheral insulin resistance (9). This observation, however, does not imply that hepatic steatosis associated with FHBL is benign. There are several reports of steatohepatitis, cirrhosis, and hepatocellular carcinoma in patients with FHBL and it is estimated that 5-10% of individuals with FHBL develop relatively more severe nonalcoholic steatohepatitis (6). Because of the risk of developing liver disease liver function tests should be checked every 1-2 years and a hepatic ultrasound in those with elevated liver transaminases (6). While hepatic fat accumulation is the rule, there is generally sufficient chylomicron production to handle dietary fat. However, oral fat intolerance and intestinal fat malabsorption have been reported (6). On the positive side the decrease in proatherogenic lipoproteins has been associated with a reduced risk of cardiovascular disease (10).

Given the association of FHBL and low LDL-C, Apo B has been an attractive target for drug development. Indeed, unraveling the genetic and molecular mechanisms of FHBL provided the motivation to pharmacologically antagonize Apo B synthesis for therapeutic gains. This culminated in the production of mipomersen, a synthetic single strand anti-sense oligonucleotide to Apo B (11,12). Essentially, anti-sense oligonucleotides contain approximately ~20 deoxyribonucleic acid (DNA) base pairs complementary to a unique messenger ribonucleic acid (mRNA) sequence. The hybridization of the anti-sense oligonucleotide to the mRNA of interest leads to its catabolism via RNase H1, with markedly reduced mRNA levels and ultimately reduced target protein levels. In this case, mipomersen binds to Apo B mRNA leading to reduced production of the protein, and mimicking (albeit to a lesser extent) FHBL. Mipomersen is the first anti-sense oligonucleotide approved by the United States Food and Drug Administration (FDA) and was commercialized in 2013 with a limited indication for adjunctive LDL-C lowering in patients with homozygous familial hypercholesterolemia (HoFH) (12). It is an injectable agent administered subcutaneously once a week. In the clinical trials, mipomersen was associated with a reduction of LDL-C by 21% in subjects with HoFH and 33% in subjects with heterozygous familial hypercholesterolemia (HeFH) (12). Interestingly, it was also found to lower Lp(a) by 21- 23% (12). While it is highly efficacious in LDL-C lowering, it has side effects, many of which can be predicted based on the experience with FHBL (e.g., hepatic steatosis, elevated liver enzymes) (12). It is also associated with injection site reactions in a considerable number of subjects (12). In May 2018 sales were discontinued due to safety concerns related to increased liver transaminases and fatty liver.

Homozygous hypobetalipoproteinemia (HHBL) is extremely rare (6). These patients are homozygous or compound heterozygous for mutations in the Apo B gene. The clinical manifestations mimic ABL (see below) (6).

ABETALIPOPROTEINEMIA  

Abetalipoproteinemia (ABL) is a rare autosomal recessive disorder characterized by very low plasma concentrations of triglyceride and cholesterol (under 30 mg/dL) and undetectable levels of LDL and Apo B (1,7,13,14). The incidence of ABL is < 1 in 1,000,000. HDL-C levels are usually normal or modestly reduced. It is due to mutations in the gene that codes for microsomal triglyceride transfer protein (MTTP) (7,13-15). MTTP lipidates nascent Apo B in the endoplasmic reticulum to produce VLDL and chylomicrons in the liver and small intestine, respectively (15,16). Unlipidated Apo B is targeted for proteasomal degradation leading to the absence of Apo B containing lipoproteins in the plasma (and thus markedly reduced levels of LDL-C and triglycerides) (15,16). Similar to FHBL, VLDL production is inhibited (14). The reduced triglyceride export from the liver leads to hepatic steatosis, which rarely may progress to steatohepatitis, fibrosis, and cirrhosis (1,9,13). Additionally, lack of MTTP facilitated lipidation of chylomicrons in the small intestine results in lipid accumulation in enterocytes with associated malabsorption, steatorrhea, and diarrhea (1,7,13). The malabsorption and diarrhea lead to failure to thrive during infancy (1,7,13). A decrease in dietary fat can reduce the gastrointestinal symptoms. Acanthocytosis may encompass 50% of circulating red blood cells (red blood cells with spiked cell membranes, due to thorny projections) due to alterations in the lipid composition and fluidity of red cell membranes (1,13,14). An additional issue of importance related to ABL is deficiency of fat-soluble vitamins (1,13). Early diagnosis of ABL and homozygous hypobetalipoproteinemia is extremely important as vitamin E deficiency culminates in atypical retinitis pigmentosa, spinocerebellar degeneration with ataxia, vitamin K deficiency can lead to a significant bleeding diathesis, vitamin A deficiency can contribute to eye disorders, and vitamin D deficiency can lead to defects in bone formation (1,13). High dose supplementation with fat soluble vitamins early in life can prevent or delay these devastating complications (Table 3) (7,13). Additional treatment measures include a low-fat diet and supplementation with essential fatty acids (Table 3) (7,13).

Derived from (1)

Given the very low level of atherogenic lipoproteins and lipids associated with ABL, there was interest in inhibiting MTTP therapeutically. Lomitapide is an oral MTP inhibitor that has been developed over the course of many years (12,17). In early trials, it was tested at a relatively high dose and the side effect profile was prohibitive (nausea, flatulence, and diarrhea). The more recent clinical trial program tested lower doses with drug titration in subjects with Homozygote Familial Hypercholesterolemia (HoFH) (12,17). On an intention to treat basis, LDL-C was decreased by 40% and apolipoprotein B by 39% (12). In patients who were actually taking lomitapide, LDL-C levels were reduced by 50% (12). In addition to decreasing LDL-C levels, non-HDL-C levels were decreased by 50%, Lp(a) by 15%, and triglycerides by 45% (12). Lomitapide received the same limited indication as mipomersen for adjunctive treatment of patients with HoFH (12). Besides the gastrointestinal issues already alluded to, its side effect profile includes hepatic steatosis (12). Its long-term safety has not been established.

PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 (PCSK9)

Proprotein convertase subtilisin/ kexin type 9 (PCSK9) belongs to the proprotein convertase class of serine proteases (18-20). After synthesis, PCSK9 undergoes autocatalytic cleavage. This step is required for secretion, most likely because the prodomain functions as a chaperone and facilitates folding (18,19). PCSK9 is associated with LDL particles and the LDL-receptor (LDLR) (20). In 2003, Abifadel reported the seminal work that mapped PCSK9 as the third locus for autosomal dominant hypercholesterolemia (Familial Hypercholesterolemia- FH) (21). This finding revealed a previously unknown actor involved in cholesterol homeostasis and served to launch a series of investigations into PCSK9 biology. As it turns out, PCSK9 functions as a central regulator of plasma LDL-C concentration (18-20). It binds to the LDLR and targets it for destruction in the lysosome (18-20). Overactivity of PCSK9 results in a decrease in LDLR and an increase in LDL-C levels while decreased activity of PCSK9 results in an increase in LDLR and a decrease in LDL-C.

Since the discovery of gain-of-function mutations in PCSK9 as a cause of FH, investigators have also uncovered loss of function mutations of PCSK9. Loss-of-function mutations in PCSK9 are associated with low LDL-C levels and markedly reduced ASCVD (18,19). In African Americans 2.6 percent had nonsense mutations in PCSK9 that resulted in a 28 percent reduction in LDL-C and an 88 percent reduction in the risk of coronary heart disease (22). The hypolipidemia is not associated with liver abnormalities or other disorders. Interestingly, rare individuals homozygous or compound heterozygotes for loss of function mutations in PCSK9 have been reported with extremely low levels of LDL-C (~15 mg/dL), normal health and reproductive capacity, and no evidence of neurologic or cognitive dysfunction (20,23,24). Collectively, these observations served as further motivation to pursue antagonism of PCSK9 as a therapeutic target. Antagonizing PCSK9 would prolong the lifespan of LDLR, leading to significant reductions in plasma LDL-C levels. Two fully human monoclonal antibodies (alirocumab and evolocumab) targeting PCSK9 became commercially available in 2015 and inclisiran, a small interfering RNA that inhibits translation of PCSK9 is also available. Other approaches to inhibit PCSK9 are under investigation.  

FAMILIAL COMBINED HYPOLIPIDEMIA   

Familial combined hypolipidemia (FCH) is due to loss of function mutations in the gene encoding angiopoietin-like protein 3 (ANGPTL3) (25,26). ANGPTL3 inhibits various lipases, such as lipoprotein lipase and endothelial lipase (25,26). Therefore, loss of function mutations in ANGPTL3 relinquishes this inhibition increasing the activity of lipases resulting in more efficient metabolism of VLDL and HDL particles (25,26). In addition, to increasing VLDL clearance the secretion of VLDL is also decreased due to a decrease in free fatty acid flux to the liver (25). LDL clearance is increased but the mechanism remains to be fully elucidated (25). Studies have suggested that ANGPTL3 inhibition lowers LDL-C by limiting LDL particle production due to ANGPTL3 inhibition and increased endothelial lipase activity reducing VLDL-lipid content and size, generating remnant particles that are efficiently removed from the circulation rather than being further metabolized to LDL (27).

Clinically, FCH manifests as panhypolipidemia (decreased triglycerides, LDL-C, HDL-C, apo B, and apo A-I) (25,26,28). Interestingly, heterozygotes for certain nonsense mutations in the first exon of ANGPTL3 have moderately reduced LDL-C and triglyceride levels while compound heterozygotes have significant reductions in HDL-C as well (25,26).  Homozygosity or compound heterozygosity for other loss-of-function mutations in exon 1 of ANGPTL3 have no detectable ANGPTL3 in plasma and striking reductions of atherogenic lipoproteins with HDL particles containing only apo A-I and preß-HDL. Individuals who are heterozygous for the loss of function mutations in ANGPTL3 have significantly reduced LDL-C and triglyceride levels and a reduced risk of atherosclerosis (25,26,28).

A pooled analysis of cases of familial combined hypolipidemia was published 2013 (29). One hundred fifteen individuals carrying 13 different mutations in the ANGPTL3 gene (14 homozygotes, 8 compound heterozygotes, and 93 heterozygotes) and 402 controls were evaluated. Homozygotes and compound heterozygotes (two mutant alleles) had no measurable ANGPTL3 protein. In heterozygotes, ANGPTL3 was reduced by 34-88%, according to genotype. All cases (homozygotes and heterozygotes) demonstrated significantly lower concentrations of all plasma lipoproteins (except for Lp(a)) as compared to controls. Familial combined hypolipidemia is not associated with any comorbidity. In fact, the prevalence of fatty liver was the same as controls. However, ANGPTL3 deficiency is associated with a reduced risk of cardiovascular disease (25,30).

Recently, evinacumab, a human monoclonal antibody against ANGPTL3, was approved for the treatment of Homozygous Familial Hypercholesterolemia (12). Evinacumab decreases LDL-C levels by mechanisms independent of LDL receptor activity (12).

CHYLOMICRON RETENTION DISEASE

Chylomicron retention disease (CMRD), known also as Anderson’s disease for the individual who first described the condition in 1961, is a rare inherited lipid malabsorption syndrome (31,32). It is due to mutations in the SAR1B gene which codes for the protein SAR1b, a small GTPase, involved in intracellular protein trafficking (31). Mutations in SAR1b result in the failure of pre-chylomicrons to move from the endoplasmic reticulum to the golgi (31). This disorder usually presents in young infants with diarrhea, steatorrhea, abdominal distention, and failure to thrive, which can improve with a low-fat diet (1,31,32). Patients with CMRD demonstrate a specific autosomal recessive hypocholesterolemia that differs from other familial hypocholesterolemias. CMRD is associated with a 50% reduction in both plasma LDL-C and HDL-C with normal fasting triglyceride levels (31,32). Mutations in SAR1B do not affect VLDL secretion by the liver. The decrease in HDL-C is postulated to be due to a decrease in Apo A-I secretion and cholesterol efflux by the small intestine (31). The mechanism accounting for the decrease in LDL-C is not clear. The usual increase in triglycerides and chylomicron levels following a fat meal is blocked (31). The duodenal mucosa is white on endoscopy and intestinal biopsy reveals cytosolic lipid droplets and lipoprotein-sized particles in enterocytes (31). As one would expect the absorption of fat-soluble vitamins (A, D, K, and E) and essential fatty acids is impaired (31,32). Neurological and eye manifestations are milder and occur at an older age compared to abetalipoproteinemia (1). Red blood cell acanthosis is rare (1). Heterozygotes with mutations in SAR1B are unaffected.

Treatment for individuals with CMRD is similar to that described above for individuals with ABL (32).

ACKNOWLEDGEMENTS

This work was supported by grants from the Northern California Institute for Research and Education.

REFERENCES

1. Bredefeld C, Hussain MM, Averna M, Black DD, Brin MF, Burnett JR, Charriere S, Cuerq C, Davidson NO, Deckelbaum RJ, Goldberg IJ, Granot E, Hegele RA, Ishibashi S, Karmally W, Levy E, Moulin P, Okazaki H, Poinsot P, Rader DJ, Takahashi M, Tarugi P, Traber MG, Di Filippo M, Peretti N. Guidance for the diagnosis and treatment of hypolipidemia disorders. J Clin Lipidol 2022; 16:797-812
2. Rimbert A, Vanhoye X, Coulibaly D, Marrec M, Pichelin M, Charriere S, Peretti N, Valero R, Wargny M, Carrie A, Lindenbaum P, Deleuze JF, Genin E, Redon R, Rollat-Farnier PA, Goxe D, Degraef G, Marmontel O, Divry E, Bigot-Corbel E, Moulin P, Cariou B, Di Filippo M. Phenotypic Differences Between Polygenic and Monogenic Hypobetalipoproteinemia. Arterioscler Thromb Vasc Biol 2021; 41:e63-e71
3. Blanco-Vaca F, Martin-Campos JM, Beteta-Vicente A, Canyelles M, Martinez S, Roig R, Farre N, Julve J, Tondo M. Molecular analysis of APOB, SAR1B, ANGPTL3, and MTTP in patients with primary hypocholesterolemia in a clinical laboratory setting: Evidence supporting polygenicity in mutation-negative patients. Atherosclerosis2019; 283:52-60
4. Balder JW, Rimbert A, Zhang X, Viel M, Kanninga R, van Dijk F, Lansberg P, Sinke R, Kuivenhoven JA. Genetics, Lifestyle, and Low-Density Lipoprotein Cholesterol in Young and Apparently Healthy Women. Circulation 2018; 137:820-831
5. Bredefeld C, Peretti N, Hussain MM, Medical Advisory P. New Classification and Management of Abetalipoproteinemia and Related Disorders. Gastroenterology 2021; 160:1912-1916
6. Burnett JR, Hooper AJ, Hegele RA. APOB-Related Familial Hypobetalipoproteinemia. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, Amemiya A, eds. GeneReviews((R)). Seattle (WA) 2021.
7. Hooper AJ, Burnett JR. Update on primary hypobetalipoproteinemia. Curr Atheroscler Rep 2014; 16:423
8. Hooper AJ, van Bockxmeer FM, Burnett JR. Monogenic hypocholesterolaemic lipid disorders and apolipoprotein B metabolism. Crit Rev Clin Lab Sci 2005; 42:515-545
9. Welty FK. Hypobetalipoproteinemia and abetalipoproteinemia: liver disease and cardiovascular disease. Curr Opin Lipidol 2020; 31:49-55
10. Peloso GM, Nomura A, Khera AV, Chaffin M, Won HH, Ardissino D, Danesh J, Schunkert H, Wilson JG, Samani N, Erdmann J, McPherson R, Watkins H, Saleheen D, McCarthy S, Teslovich TM, Leader JB, Lester Kirchner H, Marrugat J, Nohara A, Kawashiri MA, Tada H, Dewey FE, Carey DJ, Baras A, Kathiresan S. Rare Protein-Truncating Variants in APOB, Lower Low-Density Lipoprotein Cholesterol, and Protection Against Coronary Heart Disease. Circ Genom Precis Med 2019; 12:e002376
11. Crooke ST, Geary RS. Clinical pharmacological properties of mipomersen (Kynamro), a second generation antisense inhibitor of apolipoprotein B. Br J Clin Pharmacol 2013; 76:269-276
12. Feingold KR. Cholesterol Lowering Drugs. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, Dungan K, Grossman A, Hershman JM, Hofland J, Kalra S, Kaltsas G, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrere B, McGee EA, McLachlan R, Morley JE, New M, Purnell J, Sahay R, Singer F, Stratakis CA, Trence DL, Wilson DP, eds. Endotext. South Dartmouth (MA) 2021.
13. Burnett JR, Hooper AJ, Hegele RA. Abetalipoproteinemia. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, Amemiya A, eds. GeneReviews((R)). Seattle (WA)2018.
14. Lee J, Hegele RA. Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management. J Inherit Metab Dis 2014; 37:333-339
15. Wetterau JR, Lin MC, Jamil H. Microsomal triglyceride transfer protein. Biochim Biophys Acta 1997; 1345:136-150
16. Hussain MM, Shi J, Dreizen P. Microsomal triglyceride transfer protein and its role in apoB-lipoprotein assembly. J Lipid Res 2003; 44:22-32
17. Cuchel M, Rader DJ. Microsomal transfer protein inhibition in humans. Curr Opin Lipidol 2013; 24:246-250
18. Debose-Boyd RA, Horton JD. Opening up new fronts in the fight against cholesterol. Elife 2013; 2:e00663
19. Seidah NG, Awan Z, Chretien M, Mbikay M. PCSK9: a key modulator of cardiovascular health. Circ Res 2014; 114:1022-1036
20. Shapiro MD, Tavori H, Fazio S. PCSK9: From Basic Science Discoveries to Clinical Trials. Circ Res 2018; 122:1420-1438
21. Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derre A, Villeger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003; 34:154-156
22. Cohen JC, Boerwinkle E, Mosley TH, Jr., Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006; 354:1264-1272
23. Zhao Z, Tuakli-Wosornu Y, Lagace TA, Kinch L, Grishin NV, Horton JD, Cohen JC, Hobbs HH. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet 2006; 79:514-523
24. Cariou B, Ouguerram K, Zair Y, Guerois R, Langhi C, Kourimate S, Benoit I, Le May C, Gayet C, Belabbas K, Dufernez F, Chetiveaux M, Tarugi P, Krempf M, Benlian P, Costet P. PCSK9 dominant negative mutant results in increased LDL catabolic rate and familial hypobetalipoproteinemia. Arterioscler Thromb Vasc Biol 2009; 29:2191-2197
25. Arca M, D'Erasmo L, Minicocci I. Familial combined hypolipidemia: angiopoietin-like protein-3 deficiency. Curr Opin Lipidol 2020; 31:41-48
26. Kersten S. Angiopoietin-like 3 in lipoprotein metabolism. Nat Rev Endocrinol 2017; 13:731-739
27. Adam RC, Mintah IJ, Alexa-Braun CA, Shihanian LM, Lee JS, Banerjee P, Hamon SC, Kim HI, Cohen JC, Hobbs HH, Van Hout C, Gromada J, Murphy AJ, Yancopoulos GD, Sleeman MW, Gusarova V. Angiopoietin-like protein 3 governs LDL-cholesterol levels through endothelial lipase-dependent VLDL clearance. J Lipid Res2020; 61:1271-1286
28. Burnett JR, Hooper AJ, Hegele RA. Familial Combined Hypolipidemia. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, eds. GeneReviews((R)). Seattle (WA) 2023.
29. Minicocci I, Santini S, Cantisani V, Stitziel N, Kathiresan S, Arroyo JA, Marti G, Pisciotta L, Noto D, Cefalu AB, Maranghi M, Labbadia G, Pigna G, Pannozzo F, Ceci F, Ciociola E, Bertolini S, Calandra S, Tarugi P, Averna M, Arca M. Clinical characteristics and plasma lipids in subjects with familial combined hypolipidemia: a pooled analysis. J Lipid Res 2013; 54:3481-3490
30. Dewey FE, Gusarova V, Dunbar RL, O'Dushlaine C, Schurmann C, Gottesman O, McCarthy S, Van Hout CV, Bruse S, Dansky HM, Leader JB, Murray MF, Ritchie MD, Kirchner HL, Habegger L, Lopez A, Penn J, Zhao A, Shao W, Stahl N, Murphy AJ, Hamon S, Bouzelmat A, Zhang R, Shumel B, Pordy R, Gipe D, Herman GA, Sheu WHH, Lee IT, Liang KW, Guo X, Rotter JI, Chen YI, Kraus WE, Shah SH, Damrauer S, Small A, Rader DJ, Wulff AB, Nordestgaard BG, Tybjaerg-Hansen A, van den Hoek AM, Princen HMG, Ledbetter DH, Carey DJ, Overton JD, Reid JG, Sasiela WJ, Banerjee P, Shuldiner AR, Borecki IB, Teslovich TM, Yancopoulos GD, Mellis SJ, Gromada J, Baras A. Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease. N Engl J Med 2017; 377:211-221
31. Levy E, Poinsot P, Spahis S. Chylomicron retention disease: genetics, biochemistry, and clinical spectrum. Curr Opin Lipidol 2019; 30:134-139
32. Sissaoui S, Cochet M, Poinsot P, Bordat C, Collardeau-Frachon S, Lachaux A, Lacaille F, Peretti N. Lipids Responsible for Intestinal or Hepatic Disorder: When to Suspect a Familial Intestinal Hypocholesterolemia? J Pediatr Gastroenterol Nutr 2021; 73:4-8

ABSTRACT

Hypertriglyceridemia (HTG) can result from a variety of causes. Mild to moderate HTG tracks along with the metabolic syndrome, obesity and diabetes. HTG can be the result of multiple small gene variants or secondary to several diseases and drugs. Severe HTG with plasma triglyceride (TG) levels >1000-1500 mg/dL typically results from: (1) rare variants in the lipoprotein lipase (LPL) complex, where it is termed the familial chylomicronemia syndrome (FCS), and (2) the co-existence of genetic and secondary forms of HTG, termed the multifactorial chylomicronemia syndrome (MFCS), which is a much more common cause of severe HTG.  Mild to moderate HTG is associated with an increased risk of premature cardiovascular disease (CVD), while severe HTG can lead to pancreatitis as well as an increased risk of premature CVD. Appropriate management of the patient with HTG requires knowledge of the likely cause of the HTG, to prevent itscomplications.

PHYSIOLOGY

A detailed overview of lipoprotein physiology is provided in the Endotext chapter on Lipoprotein Metabolism (1).  Here we will briefly review some aspects the metabolism of the triglyceride (TG)-rich lipoproteins, very low-density lipoproteins (VLDL) and chylomicrons (CM) of particular relevance to this chapter.

Secretion of TG-rich Lipoproteins Into Plasma

TGs are transported through plasma as VLDL), which transport TGs primarily made in the liver, and as CM, which transport dietary (exogenous) fat.  VLDL secretion by the liver is regulated in several ways.  Each VLDL particle has one ApoB100 molecule, making ApoB100 availability a key determinant of the number of VLDL particles, and hence, TG secretion by the liver.  In addition to one molecule of ApoB-100, each VLDL particle contains multiple copies of other apolipoproteins, together with varied amounts of TGs, cholesteryl esters, and phospholipids.  The extent of TG synthesis is in part determined by the flux of free fatty acids (FFA) to the liver.  The addition of TG to the developing VLDL particle in the endoplasmic reticulum is mediated by the enzyme microsomal triglyceride transfer protein (MTTP).  The pool of ApoB100 in the liver is not typically regulated by its level of synthesis, which is relatively constant, but by its level of degradation, which can occur in several proteolytic pathways (2). Insulin also plays a role in the regulation of VLDL secretion -  it decreases hepatic VLDL production by limiting fatty acid influx into the liver and decreases the stability of, and promotes the posttranslational degradation of ApoB100 (3).  Recent studies have shown that ApoC-III, an Apolipoprotein thought to primarily play a role in inhibiting TG removal (see below), also is involved in the assembly and secretion of VLDL (4).  VLDL particles (containing ApoB100) also increase in plasma in the postprandial state as well as CM that contain ApoB48 (5).

Consumption of dietary fat results in the formation of CM by enterocytes.  Fatty acids and monoacylglycerols that result from digestion of dietary TGs by acid and pancreatic lipases are transported into enterocytes by mechanisms that are not completely understood.  In the enterocyte, monoacylglycerol and fatty acids are resynthesized into TGs by the action of the enzymes acyl-coenzyme A: monoacylglycerol acyltransferase and acyl-coenzyme A: diacylglycerol acyltransferase 1 and 2 (DGAT 1 and 2).  The resulting TGs are packaged with ApoB48 to form CM, a process also mediated by MTTP (6).   CM then pass into the thoracic duct from where they enter plasma and acquire additional apolipoproteins.  Of particular relevance to their clearance from plasma is the acquisition of ApoC-II and ApoC-III. 

Catabolism of the TG-rich Lipoproteins

TGs in both VLDL and CM are hydrolyzed by the lipoprotein lipase (LPL) complex.  LPL is synthesized by several tissues, including adipose tissue, skeletal muscle, and cardiac myocytes.  After secretion by adipocytes, the enzyme is transported by glycosylphosphatidylinositol-anchored high-density lipoprotein–binding protein 1 (GPIHBP1) to the luminal side of the capillary endothelium, where it becomes tethered to glycosaminoglycans (GAGs). This pool of LPL is referred to as “functional LPL”, since it is available to hydrolyze TGs in both VLDL and chylomicrons. LPL can be liberated from these GAG binding sites by heparin injection. Several other proteins, reviewed in (7), regulate LPL activity. These include ApoC-II, which activates LPL, and ApoC-III, which inhibits LPL in addition to its effect on VLDL secretion alluded to earlier. Both are produced by the liver and are present on TG-rich lipoproteins.  ApoC-III also inhibits the turnover of TG-rich lipoproteins through a hepatic clearance mechanism involving the LDL receptor/LDL receptor-related protein 1 (LDLR/LRP1) axis (8).  ApoE also is present on the TG-rich lipoproteins and plays an important role in the uptake and clearance of the remnants of the TG-rich lipoproteins that result from hydrolysis of TGs in these lipoproteins. Other activators of LPL include ApoA-IV (9), ApoA-V (10-12) and lipase maturation factor 1 (LMF1) (13, 14). In addition, several members of the angiopoietin-like (ANGPTL) protein family play a role in regulating LPL activity.  ANGPTL3 is produced by the liver and is an endocrine regulator by inhibiting LPL in peripheral tissues (7, 15, 16).  ANGPTL4 is produced in several tissues (7), where it inhibits LPL in a paracrine fashion (7, 17). Both ANPGTL3 and ANGPTL4 delay the clearance of the TG-rich lipoproteins (7).

The core TGs in VLDL and chylomicrons are hydrolyzed by ApoC-II activated LPL; FFA thus formed are taken up by adipocytes and re-incorporated into TGs for storage, or in skeletal and cardiac muscle, utilized for energy. Hydrolysis of chylomicron- and VLDL-TG results in TG-poor, cholesteryl ester and ApoE-enriched particles called chylomicron and VLDL remnants, respectively, which under physiological conditions are removed by the liver by binding to LDL receptors, LDL receptor related protein, and cell surface proteoglycans (12, 18). Hepatic TG lipase and ApoA-V also are involved in the remnant clearance process (10-12, 19, 20).

The clearance of TGs from plasma is saturable when plasma TGs exceed ~500-700 mg/dL (21).  When removal mechanisms are saturated, additional chylomicrons and VLDL entering plasma cannot readily be removed and hence accumulate in the plasma. As a result, plasma TGs can increase dramatically, resulting in very high levels and the accumulation of chylomicrons in plasma obtained after an overnight fast. 

NORMAL RANGE FOR PLASMA TRIGLYCERIDES AND DEFINITION OF HYPERTRIGLYCERIDEMIA

Plasma TG levels reflect the TG content of multiple lipoprotein particles, primarily chylomicrons and VLDL. Fasting TG levels less than 150 mg/dL has been generally accepted as “normal” (22, 23). A non-fasting TG of 175mg/dL represents ~75th percentile of the normal range, and levels of ~400mg/dL represent the 97th percentile (24). Plasma TGs are heavily skewed to the right in the general population with a tail towards highest levels and vary depending upon the population mix (25). The full range of TG extends from 30mg/dL to 10,000mg/dL (22). TG levels are different between sexes, being higher in males than in females, and increase with age and development of other coexisting conditions such as central adiposity, metabolic syndrome, and diabetes (24). TG levels also vary between geographic areas, among people of different ethnic backgrounds, with higher levels observed in certain populations such as Mexicans and South Asians. Lower TG levels have been observed in people of African descent and African-Americans but this may be changing due to adoption of urban lifestyles (26). Because of this skewed distribution, logarithmic transformation is required to establish statistical normal ranges of TG levels.  There is no current widely accepted definition of elevated non-fasting TG levels, but some groups have utilized 175mg/dL as a cut point (27, 28). Due to high variability of TG levels, precise definitions for non-fasting levels are difficult to establish. It is worthwhile noting that post-prandial TG levels rarely exceed 400mg/dL even after a high fat challenge.

Normal Range Based on Risk of Complications of Hypertriglyceridemia

The major complications of hypertriglyceridemia (HTG) are (1) acute pancreatitis and (2) increased risk of atherosclerotic cardiovascular disease (ASCVD). These two complications occur at different levels of TGs, the risk of pancreatitis occurring at much higher TG levels than the risk of premature ASCVD and are discussed in detail later in this chapter. 

Normal Range According to Guidelines

Despite concerns regarding establishment of an upper limit of normal for TGs, most guidelines define values for HTG, often without a strong biological rationale. Definitions for the diagnosis of HTG provided in several guidelines are shown in Table 1.   

Cut points for HTG were first defined by the National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP). The terms mild, moderate and severe have been used based on degree of TG elevation (table 1). In general, mild to moderate HTG reflects TG levels under 500mg/dL. Severe hypertriglyceridemia (sHTG) has been arbitrarily defined by different national guidelines as either TG levels ≥500 mg/dL by the American Heart Association (AHA)/American College of Cardiology (ACC), Multispecialty Cholesterol and Canadian Cardiovascular Society Guidelines (29, 30) or TG levels ≥880 mg/dL according to the European Society of Cardiology guidelines (31). The Endocrine Society has used severe HTG for 1000 to 1999 mg/dL and very severe HTG for values >2000 mg/dL (23).  

In summary, establishing a precise definition of what constitutes abnormal TG values is fraught with difficulty.  An acceptable level for the prevention of pancreatitis is likely to be quite different from that at which CVD risk might be increased. The impact of HTG on CVD risk needs to be evaluated in the context of the family history of premature CVD, associated abnormalities of lipids and lipoproteins, and other CVD risk factors, particularly those associated with the metabolic syndrome (see below).

CAUSES AND CLASSIFICATION OF HYPERTRIGLYCERIDEMIA

In general, HTG has been classified as primary, when a genetic or familial basis is suspected, or secondary, where other conditions that raise TG levels can be identified. However, this classification is likely overly simplistic. It has become clear in the past decade that the spectrum of plasma TG levels, ranging from mild elevation to very severe HTG, is modulated by a multitude of genes working in concert with non-genetic secondary and environmental contributors. Thus, in the vast majority of individuals, mutations in multiple genes with interaction from non-genetic factors result in altered TG-rich lipoprotein synthesis and catabolism and subsequent HTG.

Historical Perspective

Phenotypic heterogeneity among patients with HTG has been historically defined by qualitative and quantitative differences in plasma lipoproteins. In the pre-genomic era, the Fredrickson classification of hyperlipoproteinemia was based on electrophoretic patterns of lipoprotein fractions (37). The phenotypes are distinguished based on the specific class or classes of accumulated TG-rich lipoprotein particles, including chylomicrons, VLDL and VLDL-remnants. This classification included 6 phenotypes, five of which included HTG in their definition (except for Frederickson type 2 A hyperlipoproteinemia, which equates with genetic primary hypercholesterolemia). It has now become apparent that except for type 1 hyperlipoproteinemia (FCS), the HTG phenotypes, particularly Frederickson type 4 and type 5 hyperlipoproteinemia, are due to the accumulation of polygenic traits predisposing to HTG. However, this classification system is dated, has neither improved clinical or scientific insight, and therefore does not find wide use at this time (22).

In 1973, Goldstein and colleagues characterized a variable pattern of lipid abnormalities in families of survivors of myocardial infarction that they termed familial combined hyperlipidemia (FCHL) (38).  At the same time, this phenotype of mixed or combined hyperlipidemia was observed in another cohort, where it was called multiple-type familial hyperlipoproteinemia (39).  Affected family members can present with hypercholesterolemia alone, HTG alone, or with elevations in both TGs and LDL. This pattern was estimated to have a population prevalence of 1-2% (40), making it the most common inherited form of dyslipidemia.

In the aforementioned study, a pattern of isolated HTG, historically called familial HTG (FHTG) also was described (38). This condition was characterized by increased TG synthesis, with secretion of normal numbers of large TG-enriched VLDL particles (41), elevated VLDL levels, but normal levels of LDL and HDL cholesterol (42).  FHTG did not appear to be associated with an increased risk of premature CVD in an early study (43), but baseline TG levels predicted subsequent CVD mortality after 20 years of follow up among relatives in families classified as having FHTG (44, 45).  

FCHL and FHTG were initially believed to be monogenic disorders (38). However, more recent genetic characterization of individuals with familial forms of HTG indicates that these are not disorders associated with variation within a single gene, but rather polymorphisms in multiple genes associated with HTG, as detailed below. Therefore, classification of FCHL and FHTG is potentially misleading. Nevertheless, it is important to note that FCHL as originally described is associated with a very high prevalence of premature CVD (43, 44, 46).   

Genetic Forms of Hypertriglyceridemia

It is now evident that clinically relevant abnormalities of plasma TG levels appear to require a polygenic foundation of common or rare genetic variants (22).  Common small-effect gene variants confer a background predisposition that interact with rare large-effect heterozygous variants in genes that govern synthesis or catabolism of TG-rich lipoproteins, or nongenetic secondary factors, leading to the expression of a more severe TG phenotype (47). Recently, the most prevalent genetic feature underlying severe HTG was shown to be the polygenic accumulation of common (rather than rare) variants—more specifically, the accumulation of TG-raising alleles across multiple SNP loci (48).

Thus, mild to moderate hypertriglyceridemic states are complex, genetically heterogeneous disorders. Mild-to-moderate HTG is typically polygenic and results from the cumulative burden of common and rare variants in more than 30 genes, as quantified by genetic risk scores. All genetic forms can be exacerbated by non-genetic factors. Because they are a consequence of interaction between multiple susceptibility genes and lifestyle factors, individuals with moderate HTG should be considered as a single group without distinction, irrespective of concomitant lipoprotein disturbances (22). Because of the complexity of these disorders, routine genetic testing is not recommended.

Pathogenesis of Genetic Forms of Hypertriglyceridemia

Genetic forms of HTG without other lipoprotein disturbances (i.e., pure HTG) are characterized by increased TG synthesis, where normal numbers of large TG-enriched VLDL particles are secreted (41, 49-51). Reduced TG clearance also has been observed in some individuals (50-52).  Affected people have elevated VLDL levels, but normal levels of LDL, and are generally asymptomatic unless clinical CVD or severe HTG develops. 

A variety of metabolic defects that differ among families are associated with the combined hyperlipidemia phenotype. The characteristic lipoprotein abnormalities are increased ApoB levels and increased number of small dense LDL particles (42), a phenotype similar to that seen in the metabolic syndrome and type 2 diabetes (53). These primary defects occur due to 1) hepatic overproduction of VLDL particles (41) due to increased ApoB synthesis in the setting of disordered adipose metabolism (54, 55), insulin resistance (41, 56-58), and liver fat accumulation, and, 2) impaired clearance of ApoB containing particles (59, 60). Increased VLDL secretion results in an elevated plasma ApoB and HTG (56).  Long residence time of VLDL particles favors the formation of small dense LDL (59). An abundance of small dense LDL particles traditionally is associated with the presence of HTG; however, these LDL characteristics remain even after correction of the HTG by treatment with fibrates (61, 62).

In addition to Apo B abnormalities, other lipoprotein disturbances include abnormal expression of ApoA-II, ApoC-III, and PCSK9.  VLDL-TG levels in combined hyperlipidemia are modulated by ApoA-II and ApoC-III (63).  Plasma PCSK9 levels are higher in these patients, and levels correlate with TG and Apo B levels (64).

Visceral adiposity appears to be an important determinant of insulin resistance, which occurs commonly in subjects with both isolated HTG (65) and combined hyperlipidemia (65-69). Other abnormalities that have been reported in clinical FCHL include impaired lipolysis due to decreased cyclic AMP dependent signaling (54, 69), abnormal adipocyte TG turnover (70), fatty liver (71), increased arterial stiffness (72), and increased carotid intimal-medial thickness (73). 

In all of the phenotypes described above, severe HTG can occur when secondary causes of HTG such as untreated diabetes, marked weight gain, or use of TG-raising drugs are present concurrently, leading to the Multifactorial Chylomicronemia Syndrome (MFCS), described later (74).

Secondary Forms of Hypertriglyceridemia

These are described in greater detail in the chapters on Secondary Disorders of Lipid and Lipoprotein Metabolism (75-78).  However, in the section where we describe MFCS we will briefly touch on some aspects of secondary forms of HTG, since they assume importance in the pathogenesis of the severe HTG seen in the MFCS, where they often co-exist in individuals with genetic forms of HTG. In our experience, the commonest secondary forms of HTG that interact with genetic forms of HTG are type 2 diabetes (usually as part of the metabolic syndrome), obesity, recent weight gain, excessive alcohol consumption, the use of drugs that can raise TGs, and chronic kidney disease (CKD)(74, 79, 80). (Table 3)

Severe Hypertriglyceridemia and the Chylomicronemia Syndrome

In the late 1960s Fredrickson, Levy and Lees (37) classified HTG into types dependent on the pattern of lipoproteins on paper electrophoresis and the presence or absence of chylomicrons in fasting plasma. They recognized that acute pancreatitis and eruptive xanthomata occurred in the presence of chylomicronemia that accumulate in what they termed Type I and Type V hyperlipoproteinemia. Chylomicrons are present in the post-prandial state, and usually are present in fasting plasma when TG levels exceed 800 mg/dL, but absent in fasting plasma below that value (81). The term chylomicronemia syndrome was first used to describe a constellation of clinical findings such as abdominal pain, acute pancreatitis, eruptive xanthoma and lipemia retinalis that occurred in association with very high TG levels (82). Two groups of conditions can lead to severe HTG and clinical manifestations of the chylomicronemia syndrome; (1) familial chylomicronemia syndrome (FCS) due to variants in the LPL complex, and (2) multifactorial chylomicronemia syndrome (MFCS), in which genetic predisposition and secondary forms of HTG co-exist.

FAMILIAL CHYLOMICRONEMIA SYNDROME (FCS)

FCS is a monogenic disorder due to variants in one or more genes of the LPL complex that affect chylomicron catabolism. FCS incidence is very rare, with an estimated prevalence ranging from 1 in 20,000 to 300,000 (83).    

Genetics: Biallelic loss of function variants in five canonical genes lead to impaired hydrolysis of TG-rich lipoproteins, with subsequent increases in chylomicron particle numbers and markedly increased TG concentrations. The most common gene affected in FCS is LPL itself, in which patients are homozygous or compound heterozygous for two defective LPL alleles. Over 180 variants that result in LPL deficiency have been described with some clustered mutations due to founder effects (84-87). Loss of function variants account for over 90% of cases (83). Many are missense variants, some in catalytically important sites and some in regions that predispose to instability of the homodimeric structure of LPL required for enzyme activity (88). However, many common LPL gene variants have been described that have no clinical phenotype (89). Variants in the APOC2 gene, encoding ApoC-II, an activator of LPL, is another cause of FCS.  Variants have been described in several families (90, 91). In FCS thus far there is no known gene variant that affects synthesis or production of TG-rich lipoproteins.

FCS can also occur from biallelic loss of function variants in other components of the LPL complex, namely APOA5, LMF1, and GPIHBP1 genes (Table 2), each of which plays an important role in determining LPL function (92). The lipoprotein phenotype in these mimics that seen in classical LPL deficiency. Loss of function variants in GPIHBP1, which directs transendothelial LPL transport and helps anchor chylomicrons to the endothelial surface near LPL, thereby providing a platform for lipolysis, has been described in several families (83).  Autoantibodies to GPIHBP1 also can lead to chylomicronemia (93). A small number of individuals with homozygous variants in Apo A-V, which stabilizes  the lipoprotein–enzyme complex thereby enhancing lipolysis (10), have been described (94). Variants in LMF1, an endoplasmic reticulum chaperone protein required for post-translational activation of LPL, have also been identified in a few individuals (95).

Clinical presentation: FCS usually manifests in childhood or early adolescence with nausea, vomiting, failure to thrive and recurrent abdominal pain in infancy and childhood. Occasionally it can present in adulthood (87) but this is often due to delayed diagnosis with median age at diagnosis being due to unfamiliarity in most healthcare providers (96). Adults may report “brain fog” or transient confusion.

Classical clinical findings include eruptive xanthomas (often seen on buttocks, back, extensor surfaces of upper limbs), lipemia retinalis, and hepatosplenomegaly. Less common symptoms of FCS can include intestinal bleeding, anemia, and neurological features such as irritability and seizures. Patients present with TG levels ≥1000 mg/dL and often much higher, due to abnormal accumulation of chylomicrons, which can be detected by the appearance of lipemic/milky plasma.  Despite prolonged overnight fasting, plasma TG levels are >1000mg/dL due to the presence of chylomicrons in the circulation as a result of impaired clearance. The most serious concern, however, is the development of acute pancreatitis, which can lead to systemic inflammatory response syndrome, multi-organ failure, and death.

 Adapted from Ref (83)

MULTIFACTORIAL CHYLOMICRONEMIA SYNDROME (MFCS)

In contrast to FCS, MFCS is more common and complex. The prevalence of MFCS is much higher than FCS and estimated to be ~1:600-1000 (84).   

Genetics: MFCS has a genetic basis, but unlike FCS (where recessive or biallelic variants in the affected genes are causative), the genetic alteration does not always result in the phenotypic expression of the trait but only increases the possibility of the risk of developing the condition. Other factors, including non-genomic effects (epigenetics, methylation), gene-gene, or gene-environment interactions can also contribute. MFCS develops due to two main types of genetic factors that increase the odds that a patient will develop very high TG levels. First, heterozygous rare large-effect variants in one of the five canonical TG metabolism genes (LPL, Apo C-II, Apo A5, LMF-1 and GPIHBP-1) can contribute to TG elevations. These variants have variable penetrance, i.e.- clinical presentation can vary from normal to severe hypertriglyceridemia.

Secondly, the presence of a high burden of common small-effect TG-raising SNPs; cumulatively, these common SNP alleles increase susceptibility for developing hypertriglyceridemia. These SNPs may have an indirect impact of the metabolism of TG-rich

Lipoproteins. There is incomplete understanding of how an excess burden of SNPs contributes to TG levels, but their prevalence in patients with severe hypertriglyceridemia has been consistently demonstrated.

Several polygenic risk scores (PRS) for TG levels have been published (97). A recent study found that 32.0% of patients had a high polygenic score of TG-raising alleles across 16 loci compared to only 9.5% of normolipidemic controls (25). When the PRS is high, there is a significantly increased risk of developing HTG but this is not diagnostic or definitive.

Secondary Causes Contributing to Severe Hypertriglyceridemia in MFCS: The most common secondary cause in the past was undiagnosed or untreated diabetes (74), although earlier detection of diabetes may be making the association of marked hyperglycemia of untreated diabetes with very severe HTG less common. In addition, individuals with the metabolic syndrome and obesity have mild to moderate HTG which can become severe HTG; weight regain following successful weight loss can lead to marked HTG (23, 84). These patients almost always have relatives with genetic forms of HTG, whose TG levels are considerably lower than the index patient with severe HTG, in whom secondary forms of HTG also are present (74).  MFCS can result from the addition of specific drugs in patients with a genetic predisposition (23). These drugs include beta-adrenergic blocking agents (selective and non-selective) and/or diuretics (thiazides and loop-diuretics such as furosemide) used for hypertension, retinoid therapy for acne, oral estrogen therapy for menopause or birth control, selective estrogen receptor modulators (particularly raloxifene) for osteoporosis or breast cancer, protease inhibitors for HIV/AIDS, atypical anti-psychotic drugs, alcohol, and possibly sertraline (84).  Rarer causes of very severe HTG include autoimmune disease (sometimes with LPL- or GPIHBP1- specific antibodies), asparaginase therapy for acute lymphoblastic leukemia (98)^, (99) and bexarotene, a RXR agonist used in the treatment of cutaneous T cell lymphoma (100).  

Following correction of treatable secondary forms of HTG in the MFCS, TG levels usually decrease to the moderately elevated levels seen in their affected relatives (101, 102).  

OTHER CONDITIONS RESULTING IN HYPERTRIGLYCERIDEMIA

Familial Dysbetalipoproteinemia (FDB or Remnant Removal Disease)

Familial dysbetalipoproteinemia, also referred to as remnant removal disease or type III hyperlipoproteinemia, is a rare autosomal recessive disorder that can present with elevated TG levels. This disorder is characterized by the accumulation of remnant lipoproteins.

PATHOGENESIS AND GENETICS

Remnant removal disease requires homozygosity for the ApoE2 genotype or a rare heterozygosity for a variant in the ApoE gene, which results in pathologic accumulation of remnant lipoproteins in the circulation due to impaired hepatic uptake of ApoE-containing lipoproteins (103). ApoE is a glycoprotein synthesized in the liver, brain and tissue macrophages and present on chylomicrons, VLDL and HDL. Apo E through interaction with the LDLR and heparan sulphate proteoglycans promotes the hepatic clearance of remnants of chylomicrons and VLDL (104); it also facilitates cholesterol efflux from macrophages to HDL (105). In humans, there are 3 common isoforms of ApoE , ApoE2, ApoE3, and ApoE4 (106).  Each differs in isoelectric point by one charge unit, ApoE4 being the most basic isoform and ApoE2 the most acidic.  ApoE3 (Cys112Arg158) is the commonest isoform.  ApoE2 (Arg158Cys) and ApoE4 (Cys112Arg) differ from ApoE3 by single amino acid substitutions at positions 158 and 112, respectively (107).  In the majority of cases (90%), remnant removal disease is associated with the E2/E2 genotype and results from impaired binding to the Apo E receptor. It is  an autosomal recessive disorder with the prevalence of ApoE2 homozygosity in Caucasian populations estimated to be about 1% (108).  Rarer ApoE variants such as ApoE3-Leiden (109) and ApoE2 (Lys1463Gln) that also can cause remnant accumulation are dominantly inherited (110) and account for 10% of cases (111, 112).  Rare APOE variants in the population, other than the APOE2 and APOE4 alleles, play an important role in the development of isolated hypercholesterolemia (113) and mixed hyperlipidemia, with and without familial dysbetalipoproteinemia (114). Thus it is becoming apparent that two different DBL phenotypes may exist- a genetic Apo E dysfunction and a multifactorial form (115). Modern prevalence of FDB is estimated at 1-2% (116).

In the absence of additional genetic, hormonal, or environmental factors, remnants do not accumulate to a degree sufficient to cause hyperlipidemia in ApoE2 homozygotes; in fact, lipid levels are commonly low. Remnant accumulation results when the E2/2 genotype is accompanied by a second genetic or acquired defect that causes overproduction of VLDL such as obesity or diabetes (117) (111, 118) , a decrease in remnant clearance, or a reduction in LDL receptor activity (e.g., hypothyroidism (119)). Thus, full phenotypic expression requires the presence of other environmental or genetic factors (120). In these circumstances, the reduced uptake of remnant lipoproteins by the liver results in reduced conversion of VLDL and intermediate density lipoproteins to LDL, with subsequent accumulation of remnant lipoproteins (121, 122), hence the term remnant removal disease.

DIAGNOSIS

Patients with remnant removal disease have roughly equivalent elevations in plasma cholesterol and TGs. The disease rarely manifests before adulthood, and in some individuals never manifests clinically. It is more common in men than in women, where expression seldom occurs before menopause, since estrogen has a protective effect in women who are ApoE2 homozygotes (108). Palmar xanthomas (Figure 1), orange lipid deposits in the palmar or plantar creases, are pathognomonic of remnant removal disease but are not always present (123). Tuberoeruptive xanthomas can be found at pressure sites on the elbows, knees and buttocks. The presence of remnant removal disease should be suspected when total cholesterol and TG levels range from 300 to 1000 mg/dL and are roughly equal in magnitude. Special diagnostic tests such as beta-quantification or lipoprotein electrophoresis are often required and are time consuming and not widely available. VLDL particles are cholesterol- enriched, which can be determined by isolation of VLDL by ultracentrifugation and by the demonstration of beta migrating VLDL on lipoprotein electrophoresis.  A VLDL-cholesterol/plasma TG ratio of <0.30 is usually observed (124).  A low ApoB/total cholesterol ratio of <0.33 also can be helpful in making the diagnosis (125). Simplified criteria for the diagnosis of DBL using a 3-step process has been proposed (126). The diagnosis of remnant removal disease should be confirmed by demonstrating the presence of the E2/E2 genotype. If the genotype result is not E2/E2, an autosomal dominant variant of APOE should be suspected. There is a high prevalence of premature coronary artery disease (127-129) and peripheral arterial disease (130-132).  Occasionally severe HTG and an increased risk of pancreatitis can develop in the presence of a concomitant secondary form of HTG or TG-raising drugs.

Figure 1. Palmar Xanthomas: Orange-yellow discoloration confined to the palmar creases.

Familial Partial Lipodystrophy (FPLD) Syndromes

A distinct entity that results in moderate and severe hypertriglyceridemia include partial lipodystrophy syndromes. Inherited lipodystrophies are a heterogeneous group of disorders considered to be rare, that manifest as complete or partial loss of white adipose tissue with accompanying severe metabolic dysregulation(133) and are reviewed elsewhere in the Endotext chapter on Lipodystrophies (134).  Loss of fat can be either localized to small discrete areas, in some cases partial with loss from extremities, or generalized with fat loss from nearly the entire body. Inherited lipodystrophies, while rare, can be autosomal dominant or recessive.  Some forms manifest at birth, while others become evident later in life.

Partial or generalized lipodystrophic disorders frequently are associated with significant metabolic derangements associated with severe insulin resistance, including HTG. The extent of fat loss sometimes determines the severity of metabolic complications (135).  HTG is a common accompaniment of many lipodystrophies, often in conjunction with low HDL-C levels.    The pathophysiology of hypertriglyceridemia in these subjects is possibly related to the reduced ability to deposit free fatty acids in adipose tissue due to its maldevelopment, and accelerated lipolysis with increased hepatic VLDL synthesis and delayed clearance (135).

Genetics: Several genes have been implicated in the manifestation of various forms including LMNA, PPARG, LIPE, CIDEC (136). In the Dunnigan variety, the most commonly identified genetic variant of FPLD, the commonest variants are in the LMNA gene and less frequently PPARG (133).  No specific genetic defect has been identified in Köbberling’s FPLD, although recent evidence suggests a heavy polygenic burden in these individuals (137, 138).

Diagnosis: Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder in which near total absence of subcutaneous adipose tissue is evident from birth.  HTG and hepatic steatosis are evident at a young age and are often difficult to control. Severe HTG, often associated with eruptive xanthoma and recurrent pancreatitis, can occur in patients with CGL. The prevalence of HTG in case series of CGL patients is over 70% (135, 139).  Plasma TGs are normal or slightly increased during early childhood, with severe HTG manifesting at puberty along with onset of diabetes mellitus. 

Familial partial lipodystrophies (FPLD) are complex metabolic disorders that are often not recognized clinically (140).  Partial lipodystrophies are characterized by partial loss of adipose tissue and significant metabolic derangements.  The Dunnigan variety of FPLD (FPLD type 2) is a rare autosomal dominant disorder in which fat loss mostly involves the extremities and the trunk.  Onset of fat loss in the buttocks and extremities occurs at puberty or late adolescence, with gain of fat to the face and neck. Acanthosis nigricans, calf muscle hypertrophy, and phlebomegaly (prominent veins) due to lack of subcutaneous fat, can be observed. Significant metabolic dysfunction including diabetes, which is often very insulin resistant, resistant hypertension, and HTG often severe and difficult to treat, can occur.  Myopathy, cardiomyopathy, and/or conduction system abnormalities can occur (141).  ASCVD risk also is increased (142, 143).

Some lipodystrophies, where fat loss appears to be proportionate to loss of total and lean body mass, do not result in dyslipidemia. Elevated TG levels have been reported in patients with atypical progeroid syndrome due to LMNA mutations (144, 145).  Of the acquired lipodystrophies, the HIV-associated form usually is characterized by more moderate HTG.  HIV-associated lipodystrophy occurs in patients receiving protease inhibitor containing highly active anti-retroviral therapy regimens (146).  Fat loss occurs in the face, buttocks, and extremities.

CONSEQUENCES OF HYPERTRIGLYCERIDEMIA

Atherosclerotic Cardiovascular Disease

EPIDEMIOLOGY

HTG has long been known to be a risk factor for ASCVD (33, 147-150), which has been confirmed in meta-analyses (45).  However, HTG also is frequently associated with low levels of HDL-cholesterol and an accumulation of remnants of the TG-rich lipoproteins, both known risk factors for ASCVD.  When adjusted for both HDL-C and non-HDL-C, which contains both remnants of the TG-rich lipoproteins and LDL, the association of TGs with ASCVD risk remained significant, although somewhat attenuated (151).  Postprandial TGs are elevated throughout the day in subjects with HTG, and postprandial TG-rich lipoproteins and their remnants also have been hypothesized to be important in the pathogenesis of atherosclerosis (150). It is therefore of interest that non-fasting TGs have been associated with ASCVD risk (150, 152, 153), despite non-fasting TGs being quite variable. However, unlike the situation with elevated LDL-C levels, the magnitude of the TG elevation does not appear to correlate with the extent of ASCVD risk. In particular, very severe HTG per se does not always appear to confer increased ASCVD risk, possibly because the chylomicrons that accumulate are too large to enter the arterial intima (154, 155). 

TRIGLYCERIDES IN THE PATHOGENESIS OF ASCVD

Although chylomicrons may be too large to enter the arterial intima, ApoE-and cholesterol-enriched remnants of the TG-rich lipoproteins can enter with ease (153) where they can bind to vascular proteoglycans, similar to LDL (156, 157).  Modification of these retained lipoproteins by either oxidative damage or enzyme digestion of some of the lipid components can liberate toxic by-products, which have been hypothesized to play a role in atherogenesis by facilitating local injury, generation of adhesion molecule, and cytokine expression and inflammation (157).  Remnants of the TG-rich lipoproteins also can be taken up by macrophages leading to the formation of foam cells, an important component of atherosclerotic plaques.  HTG also is associated with a preponderance of small, dense LDL, particles, reduced levels of HDL-C, and in the metabolic syndrome, with abnormalities of HDL composition (see earlier). Small, dense LDL can traverse the endothelial barrier more easily than large, buoyant LDL particles (158), are retained more avidly than large, buoyant LDL (159), and also are more readily oxidized (160, 161), all of which may facilitate atherogenesis. HDL particles in some hypertriglyceridemic states, e.g., in association with the metabolic syndrome, might be dysfunctional with respect to their cholesterol efflux, anti-inflammatory, and anti-oxidant properties. Moreover, a hypercoagulable state has been reported in association with both HTG and the metabolic syndrome (162). Thus, HTG might accelerate atherosclerosis by several mechanisms, all of which could increase CVD risk.

GENETIC EVIDENCE OF HYPERTRIGLYCERIDEMIA AND ATHEROSCLEROSIS

Recent human genetic studies have provided important insight into the contribution of TGs to ASCVD. Several genetic approaches, including candidate gene sequencing, GWAS of common DNA sequence variants, and genetic analysis of TG phenotypes have unraveled new proteins and gene variants involved in plasma TG regulation (163). Some genetic variants that influence TG levels appear to be associated with increased CVD risk even after adjusting for their effects on other lipid traits (164).  GWAS have identified common noncoding variants of the LPL gene locus associated with TG and CVD risk (165, 166).  A common gain-of-function mutation in the LPL gene, S447X (10% allele frequency), is associated with reduced TG levels and reduced risk of CVD (167) and an LPL variant associated with reduced TG and ApoB levels was associated with reduced CVD similar to LDL-C lowering variants, suggesting that the clinical benefit of lowering triglyceride and LDL-C levels may be proportional to the absolute change in ApoB (168).  Conversely, several loss-of-function LPL variants linked with elevated TG levels are associated with increased CVD risk (169). Variants in the TRIB1 locus have been associated with LDL, HDL-C and TG levels (166), hepatic steatosis (170) and coronary artery disease (171). Mutations that disrupt APOC3 gene function and reduce plasma ApoC-III concentration are associated with lower TG levels and decreased risk of clinical CVD (172, 173).  In contrast, carriers of rare mutations in APOA5, encoding ApoA-V, an activator of LPL, are associated with elevated TGs and with increased risk of myocardial infarction (174, 175).  Loss of function variants in ANGPTL4 that had lower TG levels also were associated with reduced CVD risk (176, 177).  Thus, exciting new human genetics findings have causally implicated TG and TG-rich lipoproteins in the development of CVD risk. In particular, the LPL pathway and its reciprocal regulators ApoC-III and ApoA-V appear to have an important influence on atherosclerotic CVD risk. However, despite this mountain of evidence demonstrating a causal relationship of TG with atherosclerosis, the possible involvement of a correlated trait, usually low HDL-C levels, or other unmeasured traits, cannot be ruled out.

CLINICAL TRIAL EVIDENCE OF TRIGLYCERIDE LOWERING AND ASCVD

In the pre-statin era, use of gemfibrozil monotherapy demonstrated cardiovascular benefit in men with coronary heart disease. However, since the advent of statins, drugs that specifically lower plasma triglyceride levels have not clearly been shown to have a benefit with cardiovascular risk reduction in clinical trials when added to background statin therapy. Reasons for this are unclear. In genetic studies to get a comparable reduction in Apo B and coronary heart disease (CHD) risk in clinical trials, a TG reduction of ~70mg/dL is required compared to a decrease in LDL-C of only 14mg/dL. Additionally, lipid alterations due to genetics are lifelong and result in much bigger reductions in CHD than a 5-year drug study. Based on genetic studies, the magnitude of TG reduction required to demonstrate cardiovascular benefit is quite large.

CARDIOVASCULAR DISEASE IN THE CHYLOMICRONEMIA SYNDROME

As described earlier, chylomicrons have been considered to be too large to penetrate the vascular endothelium and play a role in atherogenesis (152), although  remnants of the TG-rich lipoproteins may be atherogenic (152, 178-181). The incidence of CVD is low in individuals with FCS (182), although premature atherosclerosis has been documented in well characterized subjects with this disorder (183).  However, CVD risk clearly is increased in many patients with MFCS, although the exact frequency remains unclear. The frequency of CVD outcomes does not appear to relate to the magnitude of the TG elevations (184). It is not surprising that CVD is increased in MFCS considering the association between TGs and CVD that has been documented in many studies (reviewed in (150, 185, 186)).  Many subjects develop severe HTG due to the co-existence of polygenic mutations that result in mild to moderate HTG (22) with secondary causes of HTG.  Residual HTG due to these genetic disorders persists even after severely elevated TG levels have been reduced by treatment of the secondary forms of HTG and treatment of the HTG per se.  Moreover, many patients with the MFCS have other CVD risk factors such as diabetes, reduced levels of HDL-C, and hypertension, the latter resulting in use of diuretics and beta-blockers, which play a role in raising their TGs to levels at which chylomicrons accumulate due to saturation of clearance mechanisms. Therefore, strategies to prevent CVD need to be undertaken once the TGs have been lowered to a level where pancreatitis is unlikely to recur. 

Pancreatitis

Severe hypertriglyceridemia is the third most common cause of acute pancreatitis after alcohol and gallstones. The chylomicronemia syndrome describes a constellation of findings that occur with severe elevations of plasma TG levels. There is some lack of consensus as to what constitutes severe HTG, values >1000-1500 mg/dL are generally classified as severe, although some groups consider values in the 500-1000 mg/dL range also severe hypertriglyceridemia (187). 

Individuals with both FCS and MFCS often present with hypertriglyceridemia induced acute pancreatitis, which can be recurrent if triglyceride levels remain elevated persistently. Women with genetic HTG can develop severe HTG and pancreatitis during pregnancy particularly during the third trimester (188).

The pancreatitis that occurs with severe HTG can be recurrent.  In a prospective study of patients admitted with acute pancreatitis, the distribution of plasma TGs was bimodal when measured at the peak of the pain (101, 102).  TG levels <880 mg/dL were associated with gall bladder disease and chronic alcoholism, while those above 2000 mg/dL were associated with the simultaneous presence of familial and secondary forms of HTG.  It has been suggested that individuals become prone to the development of TG-induced pancreatitis at TG values between 1500-2000 mg/dL (189).  TG-induced pancreatitis has been reported with TG levels lower than 500 mg/dL(190, 191),  although in our experience this usually occurs when patients with severe HTG stopped eating some time prior to the blood draw. The frequency of severe HTG leading to acute pancreatitis varies widely from about 6-20% of subjects, possibly related to the type of patient presenting to different type of medical centers (192, 193).  Pancreatitis often is recurrent if HTG is not appreciated to be the cause and if TG levels are not adequately controlled (87). With long term multiple episodes of acute, recurrent pancreatitis, exocrine pancreatic insufficiency or insulin deficient secondary diabetes may occur. A meta-analysis of observational studies suggests that TG-induced pancreatitis has worse outcomes than pancreatitis from other causes, with an approximate doubling of renal and respiratory failure, a nearly 4-fold increase of shock and a near doubling of mortality (194). Pancreatitis due to very severe HTG also may occur during infusion of lipid emulsions for parenteral feeding (195) or with use of the anesthetic agent propofol, which is infused in a 10% fat emulsion (196). 

MECHANISM OF SEVERE HYPERTRIGLYCERIDEMIC PANCREATITIS

The mechanism by which very severe HTG leads to pancreatitis remains speculative. Suggested mechanisms include the local liberation of FFA from TGs and lysophosphatidylcholine from phosphatidycholine when pancreatic lipase encounters very high levels of TG-rich lipoproteins in the pancreatic capillaries (197). High local concentrations of FFA overwhelm the binding capacity of albumin with resultant aggregation into micellar structures with detergent properties.  Both FFA and lysophosphatidylcholine have been shown to cause chemical pancreatitis when infused into pancreatic arteries in animal models (198-200). This leads to local liberation of more lipases from the damaged pancreatic acini, resulting in a vicious cycle (198, 201).  It also has been hypothesized that increased plasma viscosity due to the presence of increased numbers of chylomicrons in the pancreatic microcirculation contributes to the development of pancreatitis (202). There also is recent evidence of gene associations in TG-induced pancreatitis; in a Chinese cohort with HTG, a CFTR variant and TNF alpha promoter polymorphism were found to be independent risk factors for developing pancreatitis (203), while another study found an increased frequency of ApoE4 (204).

DIAGNOSIS OF SEVERE HYPERTRIGLYCERIDEMIC INDUCED PANCREATITIS

The diagnosis of HTG-associated pancreatitis can be made by the presence of severely elevated TG levels in a patient with acute pancreatitis. Falsely low serum amylase levels can be encountered due to assay interference by the TG-rich lipoproteins (205). Pseudohyponatremia due to the presence of large numbers of TG-rich lipoproteins in plasma can be seen with very high TG levels. Interference with liver transaminase assays may also occur, giving spuriously high values making it difficult to exclude alcoholic liver disease (205).

With chronic chylomicronemia, patients may develop eruptive xanthomata (Figure 2). These xanthomas represent an inflammatory response to the deposition of chylomicron-associated lipids in tissues and are yellow-red papules that usually appear on the buttocks, back and extensor surfaces of the upper limbs. Histologically, these lesions contain lipid laden foamy macrophages (206).  

Figure 2. Eruptive Xanthomas. The commonest site is on the buttocks. The lesions are papular with an erythematous base. They often are itchy.

Lipemia retinalis, where the retinal vessels take on a whitish hue with pallor of the optic fundus and retina can be observed with very high TG levels (Figure 3).  There is no associated visual impairment.  

Figure 3. Lipemia retinalis. Note the pale color of the retinal vessels.

Acute recent memory loss and mental fogginess (82) can also occasionally be seen, but has not been extensively studied. Symptoms such as fatigue, blurred vision, dysesthesias, and transient ischemic attacks have been suggested to be related to hyperviscosity resulting from high TG levels (207, 208).  Hepatosplenomegaly is frequently present in FCS due to macrophage infiltration in response to the chylomicron accumulation. Fatty liver is a common finding on imaging in both FCS and MFCS.

MANAGEMENT OF SEVERE HYPERTRIGLYCERIDEMIA

Management of HTG by lifestyle and pharmacological means is discussed in detail in the Endotext chapters on The Effect of Diet on Cardiovascular Disease and Lipid and Lipoprotein Levels and Triglyceride Lowering Drugs (209, 210).  However, in this section we will make a few points specifically relevant to this chapter. 

Before initiating lifelong therapy for hypertriglyceridemia, evaluation for and treatment of reversible secondary disorders that can elevate plasma triglyceride levels is crucial. This includes appropriate management of diabetes and hypothyroidism and substituting drugs that can elevate triglyceride levels with lipid-neutral agents. Management of hypertension should include calcium channel blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and alpha-adrenergic blockers rather than beta-adrenergic blocking agents and diuretics.

Cardiovascular Disease Prevention

ASCVD risk in HTG is modulated by the presence of several other factors, including other lipoprotein abnormalities, other CVD risk factors, and family history of CVD, with some families with HTG appearing to have a greater risk of CVD than others (44). The role of TG lowering by pharmacological means remains controversial, but there is consensus that the presence of HTG imparts residual risk after LDL has been adequately lowered with statins.

Statins: The best clinical trial data currently available for the prevention of ASCVD in patients with HTG demonstrate that statins are likely to confer the most benefit, even though their primary mode of action is not to reduce plasma TGs, nor are they very effective in so doing (211).  In patients with elevated TG levels statins will result in a significant decrease in TG levels. Based on the results of the IMPROVE-IT trial (212), the addition of ezetimibe may be of additional benefit.

Fibrates: Fibrates such as gemfibrozil and fenofibrate, are PPAR-α agonists, and very effective in lowering plasma TG levels (by up to 50%).  Several studies have failed to demonstrate a benefit of fibrates on ASCVD events, either alone or in combination with statins.  However, participants in these studies were not confined to individuals with HTG.  Nonetheless, post-hoc analysis showed that subgroups of subjects who had mild HTG >200mg/dL and LDL-C <34mg/dL had a significant reduction of ASCVD events (213-216).  In addition, the Action to Control Cardiovascular Risk in Diabetes (ACCORD)-LIPID trial, which was confined to subjects with diabetes, showed a similar outcome in the subgroups with HTG, although the trial was negative for all subjects (214).  Recently a novel selective peroxisome proliferator-activated receptor α modulator, pemafibrate, that possesses unique PPARα activity and selectivity (217), was evaluated in individuals with HTG and diabetes in the Pemafibrate to Reduce Cardiovascular OutcoMes by Reducing Triglycerides IN patiENts With diabetes (PROMINENT) trial. Patients with type 2 diabetes, triglyceride level 200 to 499 mg/dL and HDL-C of </=40 mg/dL were assigned to pemafibrate or placebo. Unfortunately, pemafibrate failed to demonstrate cardiovascular benefit in patients with type 2 diabetes and mild to moderate HTG despite significantly lowering triglyceride levels (218).  Thus, addition of a fibrate to a statin for cardiovascular risk reduction cannot be recommended at this time.

Omega-3 fish oil: Omega-3 (n-3) fatty acids are polyunsaturated fatty acids that lower TGs. The two main n-3 fatty acids are eicosapentanoic acid (EPA) and docosahexanoic acid (DHA) which can lower VLDL secretion and are agonists of PPARa. However, their role in ASCVD prevention also has been controversial as several RCTs of various dosages of n-3 mixtures failed to demonstrate CV benefit in mild to moderate HTG (219). The Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT), evaluated the addition of high dose icosapent ethyl (highly purified eicosapentanoic acid or EPA) compared to placebo in high-risk patients with mild to moderate HTG on statin therapy, demonstrated a surprising 25% lower CV risk in subjects. Notably this effect was independent of baseline TG levels and TG reduction.  (220).  Subsequently the STRENGTH (Statin Residual Risk Reduction With Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia) trial of n–3 fatty acid mixtures (EPA + DHA) failed to demonstrate cardiovascular benefit and was terminated early for futility (221). Similarly, use of an EPA/DHA mixture (1.8 g/d) in patients with a recent myocardial infarction in the OMega-3 fatty acids in Elderly with Myocardial Infarction (OMEMI) trial (222) also failed to meet its primary endpoint. Tissue EPA levels may be a contributor to the positive results in the REDUCE-IT study, as there is evidence that EPA inhibits inflammation, causes membrane stabilization, and decreases plaque volume. The REDUCE-IT trial has generated controversy due to use of mineral oil in the control group which resulted in an increase in both LDL-C and C-reactive protein (223, 224). Nonetheless, several current guidelines suggest addition of icosapent ethyl in addition to a statin for residual hypertriglyceridemia in high-risk individuals (those with known ASCVD or diabetes with additional risk factors).

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Niacin: Niacin effectively lowers triglycerides and LDL-C while raising HDL-C. Niacin inhibits lipolysis in adipocytes, therefore decreasing the available fatty acids for VLDL synthesis. However, it has fallen out of favor for ASCVD risk reduction. Two RCTs, Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) and Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) demonstrated no benefit to the addition of niacin to statins for decreasing cardiovascular risk. However, it is important to note that neither of these trials were confined to subjects with high TG levels. Therefore, due to the lack of efficacy and potential for increasing insulin resistance, niacin is not recommended for treatment of HTG.

Newer Therapies for HTG

Apo C-III Inhibitors: ApoC-III is an endogenous inhibitor of LPL, by displacing ApoC-II an activator of LPL. This leads to inhibition of lipolysis and elevations in TG levels. Apo C-III can also increase TGs by LPL independent mechanisms. Currently, ApoC-III inhibitors include volanesorsen (a second-generation antisense oligonucleotide (ASO)), olezarsen (a third generation ASO), and ARO-APOC3 (a small interfering RNA), all of which are directed at APOC3 gene (225). Volanesorsen has been studied in individuals with FCS and MFCS and has been found to decrease TG levels by up to 70% from baseline and potentially prevent pancreatitis. However, thrombocytopenia and injection site reactions are common. This drug is therefore not approved for use by the FDA due to concerns of bleeding but is approved for use by the European Medicines Agency.  

Olezarsen is a third generation ASO for which early studies have been completed.

ANGPTL-3 inhibitors: ANGPTL3 is a key regulator of lipoprotein metabolism and is able to repress LPL and endothelial lipase activity, with resultant increase in TGs and TG rich lipoprotein levels (226). Homozygous loss of function variants in ANGPTL3 result in combined hypolipidemia with low TG and LDL-C levels. ANGPTL3 inhibition results in decreased LDL-C, and TGs. ANGPTL3 inhibitors include evinacumab, a monoclonal antibody, vupanorsen, an antisense oligonucleotide (ASO), and ARO-ANG3, a small-interfering ribonucleic acid (siRNA). Evinacumab has been studied in patients with sHTG. A phase 2 study of evinacumab in patients with sHTG, demonstrated significant reductions in TGs only in patients with MFCS with and without LPL mutations, but not in patients with FCS, suggesting that ANGPTL3 inhibition is dependent on presence of some LPL activity (227). In the cohort with polygenic sHTG and MCS, evinacumab 15 mg/kg IV every 4 weeks resulted in an 81.7% reduction in TGs. It should be noted that evinacumab is currently only approved for homozygous familial hypercholesterolemia.

Management of Severe HTG-Induced Pancreatitis

Because of the low frequency of severe HTG in the general population, and because only some patients with severe HTG develop pancreatitis, large random controlled clinical trials are difficult to perform and unlikely to be undertaken in the foreseeable future. Therefore, therapeutic decisions need to be based on less stringent criteria than might otherwise be desirable.  However, keeping TG levels <500 mg/dL should prevent the onset of TG-induced pancreatitis (187, 228, 229). 

ACUTE MANAGEMENT

The clinical presentation of HTG-induced pancreatitis is similar to that from other causes of acute pancreatitis and can be preceded by episodic nausea, epigastric pain radiating through to the back, and increasing heart-burn. Individuals with recurrent acute pancreatitis may present without severe elevations in pancreatic enzymes (230). The immediate goal is to lower TGs in hospitalized patients.  Management is similar to the management of non-TG induced pancreatitis, which includes cessation of all oral intake for pancreatic rest, fluid resuscitation, pain management, and management of metabolic abnormalities. TGs fall rapidly with discontinuation of oral intake, often to under 1000mg/dL with cessation of oral intake. With clinical improvement, oral diet advancement should be done slowly and cautiously in the hospital as this can result in rebound TG elevations. Supportive care as needed should be instituted for organ failure. Lipid emulsions for parenteral feeding should be avoided since their use will further delay clearance and exacerbate the HTG. If long term nutrition is required for very ill individuals who cannot eat, total parental nutrition without lipids should be utilized.   

Heparin: Heparin will liberate LPL into plasma from its endothelial binding sites and hence rapidly lowers TGs (231). However, it also can cause rebound HTG due to rapid degradation of released LPL (232) and increases the risk of hemorrhagic pancreatitis. Therefore, the use of heparin is not recommended (233). 

Insulin: The rationale for the use of an IV insulin infusion of regular insulin (in conjunction with IV glucose administration as needed) is that it can activate LPL and enhance clearance of TG-rich lipoproteins (234). Intravenous insulin can be beneficial in individuals with diabetes needing glycemic control. Its use in TG--induced pancreatitis without diabetes has been reported in several case reports (235-239), and has become widespread but it is unclear whether similar changes would have occurred simply by restricting oral intake without the use of insulin.  Regular insulin at 0.1-0.2 units/kg/hour with a separate iv dextrose infusion to prevent hypoglycemia in individuals without diabetes is often used. IV insulin can be stopped when TG drops to below 1000mg/dL. However, TGs will increase when the individual consumes an oral diet; therefore, caution should be exercised with slow advancement of the diet. In a study of chylomicronemia with uncontrolled diabetes, insulin infusion lowered TGs more rapidly than plasmapheresis (240).

Plasmapheresis: The use of plasmapheresis to acutely lower TGs is controversial. Plasmapheresis is extracorporeal therapy where plasma is removed and replaced; plasma is separated from the blood and discarded removing chylomicrons. Substitute fluid is replaced to maintain blood volume. The procedure is highly effective in rapidly decreasing TG levels by 85% after 1 session. However, the effect is not persistent, without evidence of long-term efficacy or mortality and morbidity benefit demonstrated. Although recommended by some (241, 242), the current evidence for the benefit of use of plasmapheresis is limited to small uncontrolled anecdotal series (243) from which no firm conclusion can be made regarding its use in acute TG-induced pancreatitis (244). A recent retrospective analysis demonstrated no benefit on length of hospital stay or mortality when therapeutic plasma exchange was added to medical management of severely elevated plasma TGs (245). TG levels fall rapidly with cessation of oral intake and use of non-lipid-containing intravenous fluids.  Plasmapheresis requires a specialized center, needs central venous access, and transient anticoagulation; it only temporarily improves TG levels without addressing the underlying cause (83). Risks include line sepsis, deep vein thrombosis, and bleeding. Therefore, we do not recommend its routine use in this situation unless clinical circumstances necessitate plasmapheresis such as severe acute necrotizing pancreatitis (246), shock, or pregnancy (247). 

LONG-TERM MANAGEMENT TO PREVENT PANCREATITIS

After TG lowering in the setting of acute pancreatitis, it is essential to determine both the primary and secondary causes of the severe HTG that precipitated the acute pancreatitis.   Continued management of any secondary form of HTG, as well as lifestyle and drug therapy to maintain low TG levels is required to prevent recurrent pancreatitis. If fasting plasma TG levels remain above 1000 mg/dL after treating or removing the precipitating causes of the severe HTG, life-long therapy with fibrates or n-3 fatty acids, as described earlier, might be considered for these patients. Limited evidence suggests that orlistat, a gastrointestinal lipase inhibitor that decreases absorption of ingested fat, thereby reducing intestinal chylomicron synthesis, may be of benefit in reducing TG levels when used in conjunction with fibrate therapy (248, 249). TG and glucose control can be particularly challenging in individuals with familial partial lipodystrophy.

Management of Specific Syndromes that Accompany Severe HTG

FAMILIAL CHYLOMICRONEMIA SYNDROME (FCS)

Treatment of FCS includes management of an acute crisis (pancreatitis) and long-term management of HTG. Management of acute HTG-induced pancreatitis is described in the previous section. Long-term management of individuals with FCS involves patient education and maintaining a very low-fat diet. Consumption of even small amounts of fat can lead to severe HTG in FCS due to the absence of functional LPL. Infants with FCS presenting with abdominal pain or failure to thrive require discontinuation of breast feeding with replacement by very low-fat formula feeding to decrease TG levels and symptoms. In children and adults with FCS, dietary fat calories should be severely restricted to control the severe HTG and abdominal pain. This translates to about 5% to 10% of total daily calories from fat, which is a major burden for these patients (250).  Medium-chain TGs, which are taken up directly by the liver after absorption and do not enter plasma as chylomicrons via the thoracic duct, are a potential alternate fat source for these patients. n-3 fatty acids can aggravate the severe HTG of FCS and therefore are contraindicated in these individuals (251, 252).  Fibrates are not efficacious in FCS (253).  There are limited studies showing that orlistat might be beneficial in patients with FCS (254, 255).  Alcohol, oral contraceptives, and other TG-elevating drugs (see Table 3) can exacerbate severe HTG and precipitate acute pancreatitis in FCS.  Successful pregnancies in patients with FCS have become more common of late (256, 257).

Alipogene tiparvovec, an adeno-associated virus LPL gene therapy that was developed and resulted in significant improvement in postprandial chylomicron metabolism in patients with FCS has been abandoned and no longer available (258), Antisense oligonucleotide inhibitors of ApoC-III (volanesorsen is approved in Europe but no in the US) and of ANGPLT3 are in development for FCS (96).

MULTIFACTORIAL CHYLOMICRONEMIA SYNDROME (MFCS)

Management of acute HTG-induced pancreatitis is described in the previous section.

Long term management: To prevent acute HTG-induced pancreatitis in MFCS, the goal is to maintain TG levels below the threshold for pancreatitis, preferably <500 mg/dL. This requires instituting lifestyle adjustments, reversal of any secondary causes of HTG, such as treatment of suboptimally managed or undiagnosed diabetes, treating hypertension with lipid neutral agents such as ACE inhibitors, ARBs, calcium channel inhibitors, or alpha blockers rather than beta-adrenergic blockers and diuretics, and discontinuing other TG-raising drugs (table 3) where possible.  Alcohol intake should be limited or eliminated, since even small amounts of alcohol can substantially raise TG levels in individuals with baseline HTG.  Attention should be paid to avoid rebound weight gain that commonly occurs after successful weight loss. Oral estrogens should be substituted by transdermal or vaginal preparations, which raise plasma TGs to a lesser extent than oral estrogens (259, 260). Residual HTG should be treated with fibrates (229), which together with management of the secondary disorder or disorders, can reduce TG levels to below the threshold for developing pancreatitis. Other agents that can be used to lower TGs alone or in combination with fibrates, include n-3 fatty acids, and high-dose statins. We do not recommend using niacin due to risk of worsening insulin resistance and lack of clinical trial data for benefit. Lifestyle measures and weight loss are important, but patients should be educated on risks of rapid weight regain after successful weight loss can be associated with rebound severe HTG. Bariatric surgery also has been used to reduce severe HTG in refractory HTG (261). Inhibition of ApoC-III or ANGPTL3, which have been shown to lower TGs in patients with severe HTG (262), may have a role to play in the future the management of severe HTG in patients with MFCS. 

REFERENCES

1. Feingold, K.R., Introduction to Lipids and Lipoproteins, in Endotext, K.R. Feingold, et al., Editors. 2021: South Dartmouth (MA).
2. Fisher, E.A., The degradation of Apolipoprotein B100: multiple opportunities to regulate VLDL triglyceride production by different proteolytic pathways. Biochim Biophys Acta, 2012. 1821(5): p. 778-81.
3. Sundaram, M. and Z. Yao, Recent progress in understanding protein and lipid factors affecting hepatic VLDL assembly and secretion. Nutr Metab (Lond), 2010. 7: p. 35.
4. Yao, Z., Human Apolipoprotein C-III - a new intrahepatic protein factor promoting assembly and secretion of very low density lipoproteins. Cardiovasc Hematol Disord Drug Targets, 2012. 12(2): p. 133-40.
5. Schneeman, B.O., et al., Relationships between the responses of triglyceride-rich lipoproteins in blood plasma containing Apolipoproteins B-48 and B-100 to a fat-containing meal in normolipidemic humans. Proc Natl Acad Sci U S A, 1993. 90(5): p. 2069-73.
6. Kindel, T., D.M. Lee, and P. Tso, The mechanism of the formation and secretion of chylomicrons. Atheroscler Suppl, 2010. 11(1): p. 11-6.
7. Kersten, S., Physiological regulation of lipoprotein lipase. Biochim Biophys Acta, 2014. 1841(7): p. 919-33.
8. Gordts, P.L., et al., ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors. J Clin Invest, 2016. 126(8): p. 2855-66.
9. Goldberg, I.J., et al., Lipoprotein ApoC-II activation of lipoprotein lipase. Modulation by Apolipoprotein A-IV. J Biol Chem, 1990. 265(8): p. 4266-72.
10. Nilsson, S.K., et al., Apolipoprotein A-V; a potent triglyceride reducer. Atherosclerosis, 2011. 219(1): p. 15-21.
11. Priore Oliva, C., et al., Inherited Apolipoprotein A-V deficiency in severe hypertriglyceridemia. Arterioscler Thromb Vasc Biol, 2005. 25(2): p. 411-7.
12. Gonzales, J.C., et al., Apolipoproteins E and AV mediate lipoprotein clearance by hepatic proteoglycans. J Clin Invest, 2013. 123(6): p. 2742-51.
13. Kroupa, O., et al., Linking nutritional regulation of Angptl4, Gpihbp1, and Lmf1 to lipoprotein lipase activity in rodent adipose tissue. BMC Physiol, 2012. 12: p. 13.
14. Lamiquiz-Moneo, I., et al., (Identification of variants in LMF1 gene associated with primary hypertriglyceridemia). Clin Investig Arterioscler, 2015.
15. Inukai, K., et al., ANGPTL3 is increased in both insulin-deficient and -resistant diabetic states. Biochem Biophys Res Commun, 2004. 317(4): p. 1075-9.
16. Shimamura, M., et al., Leptin and insulin down-regulate angiopoietin-like protein 3, a plasma triglyceride-increasing factor. Biochem Biophys Res Commun, 2004. 322(3): p. 1080-5.
17. Koster, A., et al., Transgenic angiopoietin-like (angptl)4 overexpression and targeted disruption of angptl4 and angptl3: regulation of triglyceride metabolism. Endocrinology, 2005. 146(11): p. 4943-50.
18. Foley, E.M., et al., Hepatic remnant lipoprotein clearance by heparan sulfate proteoglycans and low-density lipoprotein receptors depend on dietary conditions in mice. Arterioscler Thromb Vasc Biol, 2013. 33(9): p. 2065-74.
19. Crawford, S.E. and J. Borensztajn, Plasma clearance and liver uptake of chylomicron remnants generated by hepatic lipase lipolysis: evidence for a lactoferrin-sensitive and Apolipoprotein E-independent pathway. J Lipid Res, 1999. 40(5): p. 797-805.
20. Dichek, H.L., et al., Hepatic lipase overexpression lowers remnant and LDL levels by a noncatalytic mechanism in LDL receptor-deficient mice. J Lipid Res, 2001. 42(2): p. 201-10.
21. Brunzell, J.D., et al., Evidence for a common saturable triglyceride removal mechanism for chylomicrons and very low density lipoproteins in man. Journal of Clinical Investigation, 1973. 52: p. 1578-1585.
22. Hegele, R.A., et al., The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diabetes Endocrinol, 2014. 2(8): p. 655-66.
23. Berglund, L., et al., Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab, 2012. 97(9): p. 2969-89.
24. Subramanian, S., Approach to the Patient With Moderate Hypertriglyceridemia. J Clin Endocrinol Metab, 2022. 107(6): p. 1686-1697.
25. Dron, J.S. and R.A. Hegele, Genetics of Hypertriglyceridemia. Front Endocrinol (Lausanne), 2020. 11: p. 455.
26. Noubiap, J.J., et al., Prevalence of dyslipidaemia among adults in Africa: a systematic review and meta-analysis. Lancet Glob Health, 2018. 6(9): p. e998-e1007.
27. Laufs, U., et al., Clinical review on triglycerides. Eur Heart J, 2020. 41(1): p. 99-109c.
28. Pedersen, S.B., A. Langsted, and B.G. Nordestgaard, Nonfasting Mild-to-Moderate Hypertriglyceridemia and Risk of Acute Pancreatitis. JAMA Intern Med, 2016. 176(12): p. 1834-1842.
29. Grundy, S.M., et al., 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation, 2019. 139(25): p. e1082-e1143.
30. Pearson, G.J., et al., 2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults. Can J Cardiol, 2021. 37(8): p. 1129-1150.
31. Mach, F., et al., 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J, 2020. 41(1): p. 111-188.
32. Expert Panel on Detection, E. and A. Treatment of High Blood Cholesterol in, Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA, 2001. 285(19): p. 2486-97.
33. Miller, M., et al., Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation, 2011. 123(20): p. 2292-333.
34. Jacobson, T.A., et al., National lipid association recommendations for patient-centered management of dyslipidemia: part 1--full report. J Clin Lipidol, 2015. 9(2): p. 129-69.
35. Berglund, L., et al., Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab, 2012. 97(9): p. 2969-89.
36. Authors/Task Force, M., et al., 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR). Atherosclerosis, 2016. 253: p. 281-344.
37. Fredrickson, D., R. Levy, and R. Lees, Fat transport and lipoproteins - an integrated approach to mechanisms and disorders. N Engl J Med, 1967. 276: p. 32,94,148,215,273.
38. Goldstein, J.L., et al., Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia. J Clin Invest, 1973. 52(7): p. 1544-68.
39. Nikkila, E.A. and A. Aro, Family study of serum lipids and lipoproteins in coronary heart-disease. Lancet, 1973. 1(7810): p. 954-9.
40. Brunzell, J.D., Clinical practice. Hypertriglyceridemia. N Engl J Med, 2007. 357(10): p. 1009-17.
41. Chait, A., J.J. Albers, and J.D. Brunzell, Very low density lipoprotein overproduction in genetic forms of hypertriglyceridemia. European Journal of Clinical Investigation, 1980. 10: p. 17-22.
42. Brunzell, J.D., et al., Plasma lipoproteins in familial combined hyperlipidemia and monogenic familial hypertriglyceridemia. Journal of Lipid Research, 1983. 24: p. 147-155.
43. Brunzell, J.D., et al., Myocardial infarction in the familial forms of hypertriglyceridemia. Metabolism: Clinical and Experimental, 1976. 25: p. 313-320.
44. Austin, M.A., et al., Cardiovascular disease mortality in familial forms of hypertriglyceridemia: A 20-year prospective study. Circulation, 2000. 101: p. 2777-2782.
45. Hokanson, J.E. and M.A. Austin, Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta- analysis of population-based prospective studies. J Cardiovasc Risk, 1996. 3(2): p. 213-9.
46. McNeely, M., et al., Lipoprotein and Apolipoprotein abnormalities in familial combined hyperlipidemia: a 20-year prospective study. Atherosclerosis, 2001. 159: p. 417-481.
47. Lewis, G.F., C. Xiao, and R.A. Hegele, Hypertriglyceridemia in the genomic era: a new paradigm. Endocr Rev, 2015. 36(1): p. 131-47.
48. Dron, J.S., et al., Severe hypertriglyceridemia is primarily polygenic. J Clin Lipidol, 2019. 13(1): p. 80-88.
49. Eaton, R.P., R.C. Allen, and D.S. Schade, Overproduction of a kinetic subclass of VLDL-ApoB, and direct catabolism of VLDL-ApoB in human endogenous hypertriglyceridemia: an analytical model solution of tracer data. J Lipid Res, 1983. 24(10): p. 1291-303.
50. Grundy, S.M., et al., Transport of very low density lipoprotein triglycerides in varying degrees of obesity and hypertriglyceridemia. Journal of Clinical Investigation, 1979. 63: p. 1274-1283.
51. Beil, U., et al., Triglyceride and cholesterol metabolism in primary hypertriglyceridemia. Arteriosclerosis, 1982. 2(1): p. 44-57.
52. Sigurdsson, G., A. Nicoll, and B. Lewis, Metabolism of very low density lipoproteins in hyperlipidaemia: studies of Apolipoprotein B kinetics in man. Eur J Clin Invest, 1976. 6(2): p. 167-77.
53. Ayyobi, A.F. and J.D. Brunzell, Lipoprotein distribution in the metabolic syndrome, type 2 diabetes mellitus, and familial combined hyperlipidemia. Am J Cardiol, 2003. 92(4A): p. 27J-33J.
54. Reynisdottir, S., et al., Impaired activation of adipocyte lipolysis in familial combined hyperlipidemia. J Clin Invest, 1995. 95(5): p. 2161-9.
55. Reynisdottir, S., et al., Adipose tissue lipoprotein lipase and hormone-sensitive lipase. Contrasting findings in familial combined hyperlipidemia and insulin resistance syndrome. Arterioscler Thromb Vasc Biol, 1997. 17(10): p. 2287-92.
56. Venkatesan, S., et al., Stable isotopes show a direct relation between VLDL ApoB overproduction and serum triglyceride levels and indicate a metabolically and biochemically coherent basis for familial combined hyperlipidemia. Arteriosclerosis and Thrombosis, 1993. 13: p. 1110-1118.
57. Aitman, T., et al., Defects of insulin action on fatty acid and carbohydrate metabolism in familial combined hyperlipidemia. Arterioscler Thromb Vasc Biol, 1997. 17: p. 748-754.
58. Janus, E.D., et al., Kinetic bases of the primary hyperlipidemias:Studies of Apolipoprotein B turnover in genetically defined subjects. European Journal of Clinical Investigation, 1980. 10: p. 161-172.
59. Berneis, K.K. and R.M. Krauss, Metabolic origins and clinical significance of LDL heterogeneity. J Lipid Res, 2002. 43(9): p. 1363-79.
60. Cabezas, M.C., et al., Impaired chylomicron remnant clearance in familial combined hyperlipidemia. Arterioscler Thromb, 1993. 13(6): p. 804-14.
61. Hokanson, J.E., et al., Plasma triglyceride and LDL heterogeneity in familial combined hyperlipidemia. Arteriosclerosis and Thrombosis, 1993. 13: p. 427-434.
62. Hokanson, J.E., et al., LDL physical and chemical properties in familial combined hyperlipidemia. Arteriosclerosis, Thrombosis, and Vascular Biology, 1995. 15: p. 452-459.
63. Cruz-Bautista, I., et al., Determinants of VLDL composition and Apo B-containing particles in familial combined hyperlipidemia. Clin Chim Acta, 2015. 438: p. 160-5.
64. Brouwers, M.C. and M.M. van Greevenbroek, Lipid metabolism: the significance of plasma proprotein convertase subtilisin kexin type 9 in the elucidation of complex lipid disorders. Curr Opin Lipidol, 2011. 22(4): p. 317-8.
65. Hopkins, P.N., et al., Coronary artery disease risk in familial combined hyperlipidemia and familial hypertriglyceridemia: a case-control comparison from the National Heart, Lung, and Blood Institute Family Heart Study. Circulation, 2003. 108(5): p. 519-23.
66. Purnell, J.Q., et al., Relationship of insulin sensitivity and ApoB levels to intra-abdominal fat in subjects with familial combined hyperlipidemia. Arterioscler Thromb Vasc Biol, 2001. 21(4): p. 567-72.
67. Ascaso, J., et al., Insulin resistance in patients wtih familial combined hyperlipidemia and coronary artery disease. Am J Cardiol, 1997. 80: p. 1481-1487.
68. Castro Cabezas, M., et al., Impaired fatty acid metabolism in familial combined hyperlipidemia: a mechanism associating hepatic Apolipoprotein B overproduction and insulin resistance. J Clin Invest, 1993. 92: p. 160-168.
69. van der Kallen, C., et al., Evidence of insulin resistant lipid metabolism in adipose tissue in familial combined hyperlipidemia, but not type 2 diabetes mellitus. Atherosclerosis, 2002. 164: p. 337-346.
70. Arner, P., et al., Dynamics of human adipose lipid turnover in health and metabolic disease. Nature, 2011. 478(7367): p. 110-3.
71. Brouwers, M.C., et al., Fatty liver is an integral feature of familial combined hyperlipidaemia: relationship with fat distribution and plasma lipids. Clin Sci (Lond), 2007. 112(2): p. 123-30.
72. Brouwers, M.C., et al., Increased arterial stiffness in familial combined hyperlipidemia. J Hypertens, 2009. 27(5): p. 1009-16.
73. Keulen, E.T., et al., Increased intima-media thickness in familial combined hyperlipidemia associated with Apolipoprotein B. Arterioscler Thromb Vasc Biol, 2002. 22(2): p. 283-8.
74. Chait, A. and J.D. Brunzell, Severe hypertriglyceridemia:Role of familial and acquired disorders. Metabolism: Clinical and Experimental, 1983. 32: p. 209-214.
75. Herink, M. and M.K. Ito, Medication Induced Changes in Lipid and Lipoproteins, in Endotext, K.R. Feingold, et al., Editors. 2018: South Dartmouth (MA).
76. Feingold, K.R., The Effect of Inflammation and Infection on Lipids and Lipoproteins, in Endotext, K.R., Feingold, et al., Editors. 2022: South Dartmouth (MA).
77. Feingold, K.R., Obesity and Dyslipidemia, in Endotext, K.R. Feingold, et al., Editors. 2023: South Dartmouth (MA).
78. Feingold, K.R., The Effect of Endocrine Disorders on Lipids and Lipoproteins, in Endotext, K.R. Feingold, et al., Editors. 2023: South Dartmouth (MA).
79. Chait, A., Secondary hyperlipidemia. Journal of Clinical Pathology, 1973. 26(suppl 5): p. 68-71.
80. Chait, A. and J.D. Brunzell, Acquired hyperlipidemia (secondary dyslipoproteinemia). Endocrinology and Metabolism Clinics of North America, 1990. 19: p. 259-278.
81. Brunzell, J.D. and E.L. Bierman, Chylomicronemia syndrome.Interaction of genetic and acquired hypertriglyceridemia. Medical Clinics of North America, 1982. 66: p. 455-468.
82. Chait, A., H.T. Robertson, and J.D. Brunzell, Chylomicronemia syndrome in diabetes mellitus. Diabetes Care, 1981. 4: p. 343-348.
83. Brahm, A.J. and R.A. Hegele, Chylomicronaemia-current diagnosis and future therapies. Nat Rev Endocrinol, 2015.
84. Brunzell, J. and S. Deeb, Familial lipoprotein lipase deficiency, Apo CII deficiency, and hepatic lipase deficiency, in The Metabolic and Molecular Basis of Inherited Disease, C. Scriver, et al., Editors. 2001, McGraw-Hill Book Co.: New York. p. 2789-2816.
85. Rahalkar, A.R., et al., Novel LPL mutations associated with lipoprotein lipase deficiency: two case reports and a literature review. Can J Physiol Pharmacol, 2009. 87(3): p. 151-60.
86. Martin-Campos, J.M., et al., Molecular analysis of chylomicronemia in a clinical laboratory setting: diagnosis of 13 cases of lipoprotein lipase deficiency. Clin Chim Acta, 2014. 429: p. 61-8.
87. Blom, D.J., et al., Characterizing familial chylomicronemia syndrome: Baseline data of the APPROACH study. J Clin Lipidol, 2018. 12(5): p. 1234-1243 e5.
88. Peterson, J., et al., Structural and functional consequences of missense mutations in exon 5 of the lipoprotein lipase gene. J Lipid Res, 2002. 43(3): p. 398-406.
89. Nickerson, D.A., et al., DNA sequence diversity in a 9.7-kb region of the human lipoprotein lipase gene. Nat Genet, 1998. 19(3): p. 233-40.
90. Breckenridge, W.C., et al., Hypertriglyceridemia associated with deficiency of Apolipoprotein C-II. New England Journal of Medicine, 1978. 298: p. 1265.
91. Rabacchi, C., et al., Spectrum of mutations of the LPL gene identified in Italy in patients with severe hypertriglyceridemia. Atherosclerosis, 2015. 241(1): p. 79-86.
92. Surendran, R.P., et al., Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients with severe hypertriglyceridaemia. J Intern Med, 2012. 272(2): p. 185-96.
93. Kristensen, K.K., et al., A disordered acidic domain in GPIHBP1 harboring a sulfated tyrosine regulates lipoprotein lipase. Proc Natl Acad Sci U S A, 2018. 115(26): p. E6020-E6029.
94. Calandra, S., et al., APOA5 and triglyceride metabolism, lesson from human APOA5 deficiency. Curr Opin Lipidol, 2006. 17(2): p. 122-7.
95. Peterfy, M., Lipase maturation factor 1: a lipase chaperone involved in lipid metabolism. Biochim Biophys Acta, 2012. 1821(5): p. 790-4.
96. Baass, A., et al., Familial chylomicronemia syndrome: an under-recognized cause of severe hypertriglyceridaemia. J Intern Med, 2020. 287(4): p. 340-348.
97. Dron, J.S. and R.A. Hegele, The evolution of genetic-based risk scores for lipids and cardiovascular disease. Curr Opin Lipidol, 2019. 30(2): p. 71-81.
98. Parsons, S.K., et al., Asparaginase-associated lipid abnormalities in children with acute lymphoblastic leukemia. Blood, 1997. 89(6): p. 1886-95.
99. Tozuka, M., et al., Characterization of hypertriglyceridemia induced by L-asparaginase therapy for acute lymphoblastic leukemia and malignant lymphoma. Ann Clin Lab Sci, 1997. 27(5): p. 351-7.
100. Yadav, D. and C.S. Pitchumoni, Issues in hyperlipidemic pancreatitis. J Clin Gastroenterol, 2003. 36(1): p. 54-62.
101. Brunzell, J.D. and H.G. Schrott, The interaction of familial and secondary causes of hypertriglyceridemia:Role in pancreatitis. Transactions of the Association of American Physicians, 1973. 86: p. 245-254.
102. Brunzell, J.D. and H.G. Schrott, The interaction of familial and secondary causes of hypertriglyceridemia: role in pancreatitis. J Clin Lipidol, 2012. 6(5): p. 409-12.
103. Johansen, C.T., et al., An increased burden of common and rare lipid-associated risk alleles contributes to the phenotypic spectrum of hypertriglyceridemia. Arterioscler Thromb Vasc Biol, 2011. 31(8): p. 1916-26.
104. Schneider, W.J., et al., Familial dysbetalipoproteinemia. Abnormal binding of mutant Apoprotein E to low density lipoprotein receptors of human fibroblasts and membranes from liver and adrenal of rats, rabbits, and cows. J Clin Invest, 1981. 68(4): p. 1075-85.
105. Vedhachalam, C., et al., The C-terminal lipid-binding domain of Apolipoprotein E is a highly efficient mediator of ABCA1-dependent cholesterol efflux that promotes the assembly of high-density lipoproteins. Biochemistry, 2007. 46(10): p. 2583-93.
106. Siest, G., et al., Apolipoprotein E: an important gene and protein to follow in laboratory medicine. Clin Chem, 1995. 41(8 Pt 1): p. 1068-86.
107. Weisgraber, K.H., S.C. Rall, Jr., and R.W. Mahley, Human E Apoprotein heterogeneity. Cysteine-arginine interchanges in the amino acid sequence of the Apo-E isoforms. J Biol Chem, 1981. 256(17): p. 9077-83.
108. Smelt, A.H. and F. de Beer, Apolipoprotein E and familial dysbetalipoproteinemia: clinical, biochemical, and genetic aspects. Semin Vasc Med, 2004. 4(3): p. 249-57.
109. Dong, L.M., et al., The carboxyl terminus in Apolipoprotein E2 and the seven amino acid repeat in Apolipoprotein E-Leiden: role in receptor-binding activity. J Lipid Res, 1998. 39(6): p. 1173-80.
110. Mahley, R.W., Y. Huang, and S.C. Rall, Jr., Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia). Questions, quandaries, and paradoxes. J Lipid Res, 1999. 40(11): p. 1933-49.
111. Koopal, C., A.D. Marais, and F.L. Visseren, Familial dysbetalipoproteinemia: an underdiagnosed lipid disorder. Curr Opin Endocrinol Diabetes Obes, 2017. 24(2): p. 133-139.
112. Koopal, C., et al., Autosomal dominant familial dysbetalipoproteinemia: A pathophysiological framework and practical approach to diagnosis and therapy. J Clin Lipidol, 2017. 11(1): p. 12-23 e1.
113. Cenarro, A., et al., The p.Leu167del Mutation in APOE Gene Causes Autosomal Dominant Hypercholesterolemia by Down-regulation of LDL Receptor Expression in Hepatocytes. J Clin Endocrinol Metab, 2016. 101(5): p. 2113-21.
114. Bea, A.M., et al., Contribution of APOE Genetic Variants to Dyslipidemia. Arterioscler Thromb Vasc Biol, 2023. 43(6): p. 1066-1077.
115. Paquette, M., S. Bernard, and A. Baass, Diagnosis of remnant hyperlipidaemia. Curr Opin Lipidol, 2022. 33(4): p. 227-230.
116. Pallazola, V.A., et al., Modern prevalence of dysbetalipoproteinemia (Fredrickson-Levy-Lees type III hyperlipoproteinemia). Arch Med Sci, 2020. 16(5): p. 993-1003.
117. Mahley, R.W. and S.C. Rall, Jr., Type III hyperlipoproteinemia (dysbetalipoproteinemia):The role of Apolipoprotein E in normal and abnormal lipoprotein metabolism, in The Metabolic Basis of Inherited Disease, C.R. Scriver, et al., Editors. 1989, McGraw-Hill: New York. p. 1195.
118. Brummer, D., et al., Expression of type III hyperlipoproteinemia in patients homozygous for Apolipoprotein E-2 is modulated by lipoprotein lipase and postprandial hyperinsulinemia. J Mol Med (Berl), 1998. 76(5): p. 355-64.
119. Feussner, G. and R. Ziegler, Expression of type III hyperlipoproteinaemia in a subject with secondary hypothyroidism bearing the Apolipoprotein E2/2 phenotype. J Intern Med, 1991. 230(2): p. 183-6.
120. Breslow, J.L., et al., Studies of familial type III hyperlipoproteinemia using as a genetic marker the ApoE phenotype E2/2. J Lipid Res, 1982. 23(8): p. 1224-35.
121. Chait, A., et al., Type-III Hyperlipoproteinaemia ("remnant removal disease"). Insight into the pathogenetic mechanism. Lancet, 1977. 1(8023): p. 1176-8.
122. Chait, A., et al., Impaired very low density lipoprotein and triglyceride removal in broad beta disease: comparison with endogenous hypertriglyceridemia. Metabolism, 1978. 27(9): p. 1055-66.
123. Rothschild, M., et al., Pathognomonic Palmar Crease Xanthomas of Apolipoprotein E2 Homozygosity-Familial Dysbetalipoproteinemia. JAMA Dermatol, 2016. 152(11): p. 1275-1276.
124. Albers, J.J., G.R. Warnick, and W.R. Hazzard, Type III hyperlipoproteinemia: a comparative study of current diagnostic techniques. Clin Chim Acta, 1977. 75(2): p. 193-204.
125. Blom, D.J., F.H. O'Neill, and A.D. Marais, Screening for dysbetalipoproteinemia by plasma cholesterol and Apolipoprotein B concentrations. Clin Chem, 2005. 51(5): p. 904-7.
126. Paquette, M., et al., A simplified diagnosis algorithm for dysbetalipoproteinemia. J Clin Lipidol, 2020. 14(4): p. 431-437.
127. Morganroth, J., R.I. Levy, and D.S. Fredrickson, The biochemical, clinical, and genetic features of type III hyperlipoproteinemia. Ann Intern Med, 1975. 82(2): p. 158-74.
128. Havel, R.J. and J.P. Kane, Primary dysbetalipoproteinemia:Predominancy of a specific Apoprotein species in triglyceride-rich lipoproteins. Proceedings of the National Academy of Sciences of the USA, 1973. 70: p. 2015.
129. Koopal, C., et al., Vascular risk factors, vascular disease, lipids and lipid targets in patients with familial dysbetalipoproteinemia: a European cross-sectional study. Atherosclerosis, 2015. 240(1): p. 90-7.
130. Mahley, R. and S. Rall, Type III Hyperlipoproteinemia (Dysbetalipoproteinemia): The Role of Apolipoprotein E in Normal and Abnormal Lipoprotein Metabolism, in The Metabolic & Molecular Bases of Inherited Disease, C. Scriver, et al., Editors. 2001, McGraw-Hill: New York. p. 2835-2862.
131. Koopal, C., et al., The relation between Apolipoprotein E (APOE) genotype and peripheral artery disease in patients at high risk for cardiovascular disease. Atherosclerosis, 2016. 246: p. 187-92.
132. Paquette, M., S. Bernard, and A. Baass, Dysbetalipoproteinemia Is Associated With Increased Risk of Coronary and Peripheral Vascular Disease. J Clin Endocrinol Metab, 2022. 108(1): p. 184-190.
133. Garg, A., Clinical review#: Lipodystrophies: genetic and acquired body fat disorders. J Clin Endocrinol Metab, 2011. 96(11): p. 3313-25.
134. Akinci, B., M. Sahinoz, and E. Oral, Lipodystrophy Syndromes: Presentation and Treatment, in Endotext, K.R. Feingold, et al., Editors. 2000: South Dartmouth (MA).
135. Simha, V. and A. Garg, Inherited lipodystrophies and hypertriglyceridemia. Curr Opin Lipidol, 2009. 20(4): p. 300-8.
136. Lightbourne, M. and R.J. Brown, Genetics of Lipodystrophy. Endocrinol Metab Clin North Am, 2017. 46(2): p. 539-554.
137. Lotta, L.A., et al., Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance. Nat Genet, 2017. 49(1): p. 17-26.
138. Guillin-Amarelle, C., et al., Type 1 familial partial lipodystrophy: understanding the Kobberling syndrome. Endocrine, 2016. 54(2): p. 411-421.
139. Agarwal, A.K. and A. Garg, A novel heterozygous mutation in peroxisome proliferator-activated receptor-gamma gene in a patient with familial partial lipodystrophy. J Clin Endocrinol Metab, 2002. 87(1): p. 408-11.
140. Ajluni, N., et al., Spectrum of disease associated with partial lipodystrophy: lessons from a trial cohort. Clin Endocrinol (Oxf), 2017. 86(5): p. 698-707.
141. Subramanyam, L., V. Simha, and A. Garg, Overlapping syndrome with familial partial lipodystrophy, Dunnigan variety and cardiomyopathy due to amino-terminal heterozygous missense lamin A/C mutations. Clin Genet, 2010. 78(1): p. 66-73.
142. Hussain, I. and A. Garg, Lipodystrophy Syndromes. Endocrinol Metab Clin North Am, 2016. 45(4): p. 783-797.
143. Hussain, I., N. Patni, and A. Garg, Lipodystrophies, dyslipidaemias and atherosclerotic cardiovascular disease. Pathology, 2019. 51(2): p. 202-212.
144. Jacob, K.N., et al., Phenotypic heterogeneity in body fat distribution in patients with atypical Werner's syndrome due to heterozygous Arg133Leu lamin A/C mutation. J Clin Endocrinol Metab, 2005. 90(12): p. 6699-706.
145. Garg, A., et al., Atypical progeroid syndrome due to heterozygous missense LMNA mutations. J Clin Endocrinol Metab, 2009. 94(12): p. 4971-83.
146. Calvo, M. and E. Martinez, Update on metabolic issues in HIV patients. Curr Opin HIV AIDS, 2014. 9(4): p. 332-9.
147. Castelli, W.P., The triglyceride issue: a view from Framingham. Am Heart J, 1986. 112(2): p. 432-7.
148. Harchaoui, K.E., et al., Triglycerides and cardiovascular risk. Curr Cardiol Rev, 2009. 5(3): p. 216-22.
149. Langsted, A., et al., Nonfasting cholesterol and triglycerides and association with risk of myocardial infarction and total mortality: the Copenhagen City Heart Study with 31 years of follow-up. J Intern Med, 2011. 270(1): p. 65-75.
150. Nordestgaard, B.G. and A. Varbo, Triglycerides and cardiovascular disease. Lancet, 2014. 384(9943): p. 626-35.
151. Hokanson, J.E. and M.A. Austin, Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk, 1996. 3(2): p. 213-9.
152. Zilversmit, D.B., Atherogenesis:A postprandial phenomenon. Circulation, 1979. 60: p. 473-485.
153. Zilversmit, D.B., Atherogenic nature of triglycerides, postprandial lipidemia, and triglyceride-rich remnant lipoproteins. Clin Chem, 1995. 41(1): p. 153-8.
154. Nordestgaard, B.G. and D.B. Zilversmit, Large lipoproteins are excluded from the arterial wall in diabetic cholesterol-fed rabbits. J Lipid Res, 1988. 29(11): p. 1491-500.
155. Nordestgaard, B.G., S. Stender, and K. Kjeldsen, Reduced atherogenesis in cholesterol-fed diabetic rabbits. Giant lipoproteins do not enter the arterial wall. Arteriosclerosis, 1988. 8(4): p. 421-8.
156. Williams, K.J. and I. Tabas, The response-to-retention hypothesis of early atherogenesis. Arteriosclerosis, Thrombosis, and Vascular Biology, 1995. 15: p. 551-561.
157. Williams, K.J. and I. Tabas, The response-to-retention hypothesis of atherogenesis reinforced. Curr Opin Lipidol, 1998. 9(5): p. 471-4.
158. Krauss, R.M., Dense low density lipoproteins and coronary artery disease. Am J Cardiol, 1995. 75(6): p. 53B-57B.
159. Olin-Lewis, K., et al., ApoC-III content of ApoB-containing lipoproteins is associated with binding to the vascular proteoglycan biglycan. J Lipid Res, 2002. 43(11): p. 1969-77.
160. Chait, A., et al., Susceptibility of small, dense low density lipoproteins to oxidative modification in subjects with the atherogenic lipoprotein phenotype, pattern B. American Journal of Medicine, 1993. 94: p. 350-356.
161. Tribble, D.L., et al., Oxidative susceptibility of LDL density subfractions is related to their ubiquinol-10 and à-tocopherol content. Proceedings of the National Academy of Sciences of the USA, 1994. 91: p. 1183-1187.
162. Cornier, M.A., et al., The metabolic syndrome. Endocr Rev, 2008. 29(7): p. 777-822.
163. Rosenson, R.S., et al., Genetics and causality of triglyceride-rich lipoproteins in atherosclerotic cardiovascular disease. J Am Coll Cardiol, 2014. 64(23): p. 2525-40.
164. Do, R., et al., Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet, 2013. 45(11): p. 1345-52.
165. Waterworth, D.M., et al., Genetic variants influencing circulating lipid levels and risk of coronary artery disease. Arterioscler Thromb Vasc Biol, 2010. 30(11): p. 2264-76.
166. Teslovich, T.M., et al., Biological, clinical and population relevance of 95 loci for blood lipids. Nature, 2010. 466(7307): p. 707-13.
167. Rip, J., et al., Lipoprotein lipase S447X: a naturally occurring gain-of-function mutation. Arterioscler Thromb Vasc Biol, 2006. 26(6): p. 1236-45.
168. Ference, B.A., et al., Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants With Risk of Coronary Heart Disease. JAMA, 2019. 321(4): p. 364-373.
169. Pimstone, S.N., et al., Mutations in the gene for lipoprotein lipase. A cause for low HDL cholesterol levels in individuals heterozygous for familial hypercholesterolemia. Arterioscler Thromb Vasc Biol, 1995. 15(10): p. 1704-12.
170. Burkhardt, R., et al., Trib1 is a lipid- and myocardial infarction-associated gene that regulates hepatic lipogenesis and VLDL production in mice. J Clin Invest, 2010. 120(12): p. 4410-4.
171. Douvris, A., et al., Functional analysis of the TRIB1 associated locus linked to plasma triglycerides and coronary artery disease. J Am Heart Assoc, 2014. 3(3): p. e000884.
172. Tg, et al., Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med, 2014. 371(1): p. 22-31.
173. Jorgensen, A.B., et al., Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med, 2014. 371(1): p. 32-41.
174. Soufi, M., et al., Mutation screening of the APOA5 gene in subjects with coronary artery disease. J Investig Med, 2012. 60(7): p. 1015-9.
175. Do, R., et al., Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature, 2015. 518(7537): p. 102-6.
176. Dewey, F.E., et al., Inactivating Variants in ANGPTL4 and Risk of Coronary Artery Disease. N Engl J Med, 2016. 374(12): p. 1123-33.
177. Myocardial Infarction, G., et al., Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease. N Engl J Med, 2016. 374(12): p. 1134-44.
178. Nordestgaard, B.G., R. Wootton, and B. Lewis, Selective retention of VLDL, IDL, and LDL in the arterial intima of genetically hyperlipidemic rabbits in vivo. Molecular size as a determinant of fractional loss from the intima-inner media. Arterioscler Thromb Vasc Biol, 1995. 15(4): p. 534-42.
179. Norata, G.D., et al., Post-prandial endothelial dysfunction in hypertriglyceridemic subjects: molecular mechanisms and gene expression studies. Atherosclerosis, 2007. 193(2): p. 321-7.
180. Malloy, M.J. and J.P. Kane, A risk factor for atherosclerosis: triglyceride-rich lipoproteins. Adv Intern Med, 2001. 47: p. 111-36.
181. Mamo, J.C., S.D. Proctor, and D. Smith, Retention of chylomicron remnants by arterial tissue; importance of an efficient clearance mechanism from plasma. Atherosclerosis, 1998. 141 Suppl 1: p. S63-9.
182. Havel, R.J. and R.S. Gordon, Jr., Idiopathic hyperlipemia: metabolic studies in an affected family. J Clin Invest, 1960. 39: p. 1777-90.
183. Benlian, P., et al., Premature atherosclerosis in patients with familial chylomicronemia caused by mutations in the lipoprotein lipase gene. N Engl J Med, 1996. 335(12): p. 848-54.
184. Zafrir, B., et al., Clinical features and outcomes of severe, very severe, and extreme hypertriglyceridemia in a regional health service. J Clin Lipidol, 2018. 12(4): p. 928-936.
185. Austin, M.A. and J.E. Hokanson, Epidemiology of triglycerides, small dense low-density lipoprotein, and lipoprotein(a) as risk factors for coronary heart disease. Med Clin North Am, 1994. 78(1): p. 99-115.
186. Goldberg, I.J., R.H. Eckel, and R. McPherson, Triglycerides and heart disease: still a hypothesis? Arterioscler Thromb Vasc Biol, 2011. 31(8): p. 1716-25.
187. Brown, W.V., et al., Severe hypertriglyceridemia. J Clin Lipidol, 2012. 6(5): p. 397-408.
188. Goldberg, A.S. and R.A. Hegele, Severe hypertriglyceridemia in pregnancy. J Clin Endocrinol Metab, 2012. 97(8): p. 2589-96.
189. Brunzell, J.D., Lipoprotein lipase deficiency and other causes of the chylomicronemia syndrome, in The Metabolic Basis of Inherited Disease, C.R. Scriver, et al., Editors. 1989, McGraw-Hill: New York. p. 1165-1180.
190. Tremblay, K., et al., Etiology and risk of lactescent plasma and severe hypertriglyceridemia. J Clin Lipidol, 2011. 5(1): p. 37-44.
191. Lloret Linares, C., et al., Acute pancreatitis in a cohort of 129 patients referred for severe hypertriglyceridemia. Pancreas, 2008. 37(1): p. 13-2.
192. Cameron, J.L., et al., Acute pancreatitis with hyperlipidemia:The incidence of lipid abnormalities in acute pancreatitis. Annals of Surgery, 1973. 177: p. 483-489.
193. Farmer, R.G., et al., Hyperlipoproteinemia and pancreatitis. American Journal of Medicine, 1973. 54: p. 161-165.
194. Wang, Q., et al., Elevated Serum Triglycerides in the Prognostic Assessment of Acute Pancreatitis: A Systematic Review and Meta-Analysis of Observational Studies. J Clin Gastroenterol, 2017. 51(7): p. 586-593.
195. Mirtallo, J.M., et al., State of the art review: Intravenous fat emulsions: Current applications, safety profile, and clinical implications. Ann Pharmacother, 2010. 44(4): p. 688-700.
196. Devaud, J.C., et al., Hypertriglyceridemia: a potential side effect of propofol sedation in critical illness. Intensive Care Med, 2012. 38(12): p. 1990-8.
197. Havel, R.J., Pathogenesis, differentiation and management of hypertriglyceridemia. Adv Intern Med, 1969. 15: p. 117-54.
198. Yang, F., et al., The role of free fatty acids, pancreatic lipase and Ca+ signalling in injury of isolated acinar cells and pancreatitis model in lipoprotein lipase-deficient mice. Acta Physiol (Oxf), 2009. 195(1): p. 13-28.
199. Tsuang, W., et al., Hypertriglyceridemic pancreatitis: presentation and management. Am J Gastroenterol, 2009. 104(4): p. 984-91.
200. Valdivielso, P., A. Ramirez-Bueno, and N. Ewald, Current knowledge of hypertriglyceridemic pancreatitis. Eur J Intern Med, 2014. 25(8): p. 689-94.
201. Saharia, P., et al., Acute pancreatitis with hyperlipemia: studies with an isolated perfused canine pancreas. Surgery, 1977. 82(1): p. 60-7.
202. Seplowitz, A.H., S. Chien, and F.R. Smith, Effects of lipoproteins on plasma viscosity. Atherosclerosis, 1981. 38(1-2): p. 89-95.
203. Chang, Y.T., et al., Association of cystic fibrosis transmembrane conductance regulator (CFTR) mutation/variant/haplotype and tumor necrosis factor (TNF) promoter polymorphism in hyperlipidemic pancreatitis. Clin Chem, 2008. 54(1): p. 131-8.
204. Ivanova, R., et al., Triglyceride levels and Apolipoprotein E polymorphism in patients with acute pancreatitis. Hepatobiliary Pancreat Dis Int, 2012. 11(1): p. 96-101.
205. Durrington, P., Dyslipidaemia. Lancet, 2003. 362(9385): p. 717-31.
206. Parker, F., et al., Evidence for the chylomicron origin of lipids accumulating in diabetic eruptive xanthomas:A correlative lipid biochemical, histochemical and electron microscopic study. Journal of Clinical Investigation, 1970. 49: p. 2172-2187.
207. Rosenson, R.S., et al., Hypertriglyceridemia and other factors associated with plasma viscosity. Am J Med, 2001. 110(6): p. 488-92.
208. Inokuchi, R., et al., Hypertriglyceridemia as a possible cause of coma: a case report. J Med Case Rep, 2012. 6: p. 412.
209. Feingold, K.R., Triglyceride Lowering Drugs, in Endotext, K.R. Feingold, et al., Editors. 2021: South Dartmouth (MA).
210. Feingold K.R., The Effect of Diet on Cardiovascular Disease and Lipid and Lipoprotein Levels, in Endotext, K.R. Feingold, et al., Editors. 2021: South Dartmouth (MA).
211. Scandinavian Simvastatin Survival Study Group, Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet, 1994. 344: p. 1383-1389.
212. Cannon, C.P., et al., Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med, 2015.
213. Koskinen, P., et al., Coronary heart disease incidence in NIDDM patients in the Helsinki Heart Study. Diab Care, 1992. 15: p. 825-829.
214. ACCORD Study Group, et al., Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med, 2010. 362(17): p. 1563-74.
215. Keech, A., et al., Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet, 2005. 366(9500): p. 1849-61.
216. Bezafibrate Infarction Prevention, s., Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. Circulation, 2000. 102(1): p. 21-7.
217. Camejo, G., Phase 2 clinical trials with K-877 (pemafibrate): A promising selective PPAR-alpha modulator for treatment of combined dyslipidemia. Atherosclerosis, 2017. 261: p. 163-164.
218. Das Pradhan, A., et al., Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk. N Engl J Med, 2022. 387(21): p. 1923-1934.
219. Aung, T., et al., Associations of Omega-3 Fatty Acid Supplement Use With Cardiovascular Disease Risks: Meta-analysis of 10 Trials Involving 77917 Individuals. JAMA Cardiol, 2018. 3(3): p. 225-234.
220. Bhatt, D.L., et al., Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med, 2018.
221. Nicholls, S.J., et al., Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTH Randomized Clinical Trial. JAMA, 2020. 324(22): p. 2268-2280.
222. Kalstad, A.A., et al., Effects of n-3 Fatty Acid Supplements in Elderly Patients After Myocardial Infarction: A Randomized, Controlled Trial. Circulation, 2021. 143(6): p. 528-539.
223. Goff, Z.D. and S.E. Nissen, N-3 polyunsaturated fatty acids for cardiovascular risk. Curr Opin Cardiol, 2022. 37(4): p. 356-363.
224. Mason, R.P., S.C.R. Sherratt, and R.H. Eckel, Omega-3-fatty acids: Do they prevent cardiovascular disease? Best Pract Res Clin Endocrinol Metab, 2023. 37(3): p. 101681.
225. Zambon, A., et al., New and Emerging Therapies for Dyslipidemia. Endocrinol Metab Clin North Am, 2022. 51(3): p. 635-653.
226. Haller, J.F., et al., ANGPTL8 requires ANGPTL3 to inhibit lipoprotein lipase and plasma triglyceride clearance. J Lipid Res, 2017. 58(6): p. 1166-1173.
227. Rosenson, R.S., et al., Evinacumab in severe hypertriglyceridemia with or without lipoprotein lipase pathway mutations: a phase 2 randomized trial. Nat Med, 2023. 29(3): p. 729-737.
228. Chaudhry, R., A. Viljoen, and A.S. Wierzbicki, Pharmacological treatment options for severe hypertriglyceridemia and familial chylomicronemia syndrome. Expert Rev Clin Pharmacol, 2018. 11(6): p. 589-598.
229. Capell, W.H. and R.H. Eckel, Treatment of hypertriglyceridemia. Curr Diab Rep, 2006. 6(3): p. 230-40.
230. Yuan, G., K.Z. Al-Shali, and R.A. Hegele, Hypertriglyceridemia: its etiology, effects and treatment. CMAJ, 2007. 176(8): p. 1113-20.
231. Whayne, T.F., Jr. and J.M. Felts, Activation of lipoprotein lipase. Effects of rat serum lipoprotein fractions and heparin. Circ Res, 1970. 27(6): p. 941-51.
232. Weintraub, M., et al., Continuous intravenous heparin administration in humans causes a decrease in serum lipolytic activity and accumulation of chylomicrons in circulation. J Lipid Res, 1994. 35(2): p. 229-38.
233. Whayne, T.F., Jr., Concerns about heparin therapy for hypertriglyceridemia. Arch Intern Med, 2010. 170(1): p. 108-9; author reply 109.
234. Goldberg, I.J., Lipoprotein lipase and lipolysis: central roles in lipoprotein metabolism and atherogenesis. J Lipid Res, 1996. 37(4): p. 693-707.
235. Aryal, M.R., et al., Acute pancreatitis owing to very high triglyceride levels treated with insulin and heparin infusion. BMJ Case Rep, 2013. 2013.
236. Khan, A.S., S.U. Latif, and M.A. Eloubeidi, Controversies in the etiologies of acute pancreatitis. JOP, 2010. 11(6): p. 545-52.
237. Coskun, A., et al., Treatment of hypertriglyceridemia-induced acute pancreatitis with insulin. Prz Gastroenterol, 2015. 10(1): p. 18-22.
238. Mikhail, N., et al., Treatment of severe hypertriglyceridemia in nondiabetic patients with insulin. Am J Emerg Med, 2005. 23(3): p. 415-7.
239. Jabbar, M.A., M.I. Zuhri-Yafi, and J. Larrea, Insulin therapy for a non-diabetic patient with severe hypertriglyceridemia. J Am Coll Nutr, 1998. 17(5): p. 458-61.
240. Thuzar, M., et al., Extreme hypertriglyceridemia managed with insulin. J Clin Lipidol, 2014. 8(6): p. 630-4.
241. Szczepiorkowski, Z.M., et al., Guidelines on the use of therapeutic apheresis in clinical practice--evidence-based approach from the Apheresis Applications Committee of the American Society for Apheresis. J Clin Apher, 2010. 25(3): p. 83-177.
242. Stefanutti, C. and U. Julius, Treatment of primary hypertriglyceridemia states - General approach and the role of extracorporeal methods. Atheroscler Suppl, 2015. 18: p. 85-94.
243. Furuya, T., et al., Plasma exchange for hypertriglyceridemic acute necrotizing pancreatitis: report of two cases. Ther Apher, 2002. 6(6): p. 454-8.
244. Click, B., et al., The role of apheresis in hypertriglyceridemia-induced acute pancreatitis: A systematic review. Pancreatology, 2015. 15(4): p. 313-20.
245. Webb, C.B., et al., Effect of TPE vs medical management on patient outcomes in the setting of hypertriglyceridemia-induced acute pancreatitis with severely elevated triglycerides. J Clin Apher, 2021. 36(5): p. 719-726.
246. Koutroumpakis, E., et al., Management and outcomes of acute pancreatitis patients over the last decade: A US tertiary-center experience. Pancreatology, 2017. 17(1): p. 32-40.
247. Huang, C., et al., Clinical features and treatment of hypertriglyceridemia-induced acute pancreatitis during pregnancy: A retrospective study. J Clin Apher, 2016. 31(6): p. 571-578.
248. Wierzbicki, A.S., T.M. Reynolds, and M.A. Crook, Usefulness of Orlistat in the treatment of severe hypertriglyceridemia. Am J Cardiol, 2002. 89(2): p. 229-31.
249. Tolentino, M.C., et al., Combination of gemfibrozil and orlistat for treatment of combined hyperlipidemia with predominant hypertriglyceridemia. Endocr Pract, 2002. 8(3): p. 208-12.
250. Davidson, M., et al., The burden of familial chylomicronemia syndrome: interim results from the IN-FOCUS study. Expert Rev Cardiovasc Ther, 2017. 15(5): p. 415-423.
251. Rouis, M., et al., Therapeutic response to medium-chain triglycerides and omega-3 fatty acids in a patient with the familial chylomicronemia syndrome. Arterioscler Thromb Vasc Biol, 1997. 17(7): p. 1400-6.
252. Brunzell, J.D., Familial Lipoprotein Lipase Deficiency, in GeneReviews at GeneTests: Medical Genetics Information Resource. 2011, University of Washington: Seattle. p. 1997-2010.
253. Brunzell JD, D.S., Familial lipoprotein lipase deficiency, Apo CII deficiency and hepatic lipase deficiency., in The Metabolic and Molecular Basis of Inherited Disease, 8th edition2001, McGraw-Hill Book Co.: New York. p. 2789-2816.
254. Patni, N., C. Quittner, and A. Garg, Orlistat Therapy for Children With Type 1 Hyperlipoproteinemia: A Randomized Clinical Trial. J Clin Endocrinol Metab, 2018. 103(6): p. 2403-2407.
255. Blackett, P., et al., Lipoprotein abnormalities in compound heterozygous lipoprotein lipase deficiency after treatment with a low-fat diet and orlistat. J Clin Lipidol, 2013. 7(2): p. 132-9.
256. Tsai, E.C., et al., Potential of essential fatty acid deficiency with extremely low fat diet in lipoprotein lipase deficiency during pregnancy: A case report. BMC Pregnancy Childbirth, 2004. 4(1): p. 27.
257. Al-Shali, K., et al., Successful pregnancy outcome in a patient with severe chylomicronemia due to compound heterozygosity for mutant lipoprotein lipase. Clin Biochem, 2002. 35(2): p. 125-30.
258. Carpentier, A.C., et al., Effect of alipogene tiparvovec (AAV1-LPL(S447X)) on postprandial chylomicron metabolism in lipoprotein lipase-deficient patients. J Clin Endocrinol Metab, 2012. 97(5): p. 1635-44.
259. Sanada, M., et al., Substitution of transdermal estradiol during oral estrogen-progestin therapy in postmenopausal women: effects on hypertriglyceridemia. Menopause, 2004. 11(3): p. 331-6.
260. Hemelaar, M., et al., Oral, more than transdermal, estrogen therapy improves lipids and lipoprotein(a) in postmenopausal women: a randomized, placebo-controlled study. Menopause, 2003. 10(6): p. 550-8.
261. Hsu, S.Y., et al., Laparoscopic bariatric surgery for the treatment of severe hypertriglyceridemia. Asian J Surg, 2015. 38(2): p. 96-101.
262. Gaudet, D., et al., Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia. N Engl J Med, 2015. 373(5): p. 438-47.

ABSTRACT

Very low HDL-C levels (<20mg/dL) may be due to severe elevations in triglycerides, very poorly controlled diabetes, inflammation, infections, malignancy, liver disease, and certain medications such as anabolic steroids. Additionally, variants in multiple genes that each have a small effect but cumulatively lead to a decrease in HDL-C can result in very low HDL-C levels. Finally, rare monogenic disorders such as familial hypoalphalipoproteinemia, Tangier disease, and lecithin acyltransferase (LCAT) deficiency can lead to very low HDL-C levels. In this chapter we discuss the lipid abnormalities and clinical features of these monogenic disorders causing very low HDL-C levels. An elevated concentration of apo A-I and apo A-II is called hyperalphalipoproteinemia (HALP). HALP is classified as moderate (HDL-C levels between 80 and 100 mg/dL) or severe (HDL-C levels > 100 mg/dL). HALP is a heterogeneous condition caused by a variety of genetic and secondary conditions (for example ethanol abuse, primary biliary cirrhosis, multiple lipomatosis, emphysema, exercise, and certain drugs such as estrogens). In many individuals HALP has a polygenic origin. Monogenic HALP includes CETP deficiency, hepatic lipase deficiency, endothelial lipase deficiency, and loss of function mutations in SRB1. In this chapter we discuss the lipid abnormalities and clinical features of these monogenic disorders causing HALP.

LOW HDL CONDITIONS

The inverse relationship between HDL-C and ASCVD risk is well established but it should be recognized that while this association is consistently observed recent genetic and cardiovascular outcome studies suggest that this association is not causal (1). However, as discussed below major reductions in HDL-C induced by specific monogenic disorders may increase the risk of ASCVD.

Isolated low HDL-C levels can occur; however, it is more commonly found in association with hypertriglyceridemia and/or elevated apo B levels, typically as part of the obesity/metabolic syndrome (2). Patients with very low HDL-C (<20 mg/dL) in the absence of severe hypertriglyceridemia, very poorly controlled diabetes, inflammation, infections, malignancy, liver disease, anabolic steroids, or a paradoxical response to PPAR agonists are very rare (<1% of the population) (3,4). These individuals may have a very rare monogenic disorder associated with marked HDL deficiency, including familial hypoalphalipoproteinemia, Tangier disease, and lecithin acyltransferase (LCAT) deficiency. Table 1 summarizes the genetic, lipid, and clinical features of these monogenic low HDL conditions. Inheritance is autosomal co-dominant with heterozygotes having decreases in HDL-C levels approximately midway between normal and homozygotes (3). In some individuals the decrease in HDL-C can be polygenic i.e., variants in multiple genes that each have a small effect but cumulatively lead to a decrease in HDL-C (5).

Inheritance is autosomal co-dominant with heterozygotes having decreases in HDL-C levels approximately midway between normal and homozygotes (3). FLD- Familial Lecithin: Cholesteryl Ester Acyltransferase Deficiency; FED- Fish Eye Disease

Familial Hypoalphalipoproteinemia  

Familial hypoalphalipoproteinemia is a heterogeneous group of apolipoprotein A-I (apo A-I) deficiency states. This disorder is the rarest cause of  monogenic severe HDL deficiency (6). These various conditions are characterized by the specific apolipoprotein genes that are affected on the apo A-I/C-III/A-IV gene cluster (3). The genes for these 3 apolipoproteins (apo A-I, apo C-III, and apo A-IV) are grouped together in a cluster on human chromosome 11. In patients with apo A-I/C-III/A-IV deficiency, apoA-1 is undetectable in the plasma and is associated with marked deficiency in HDL-C, low triglyceride levels (due to apo C-III deficiency), and normal LDL-C levels (3). Heterozygotes have plasma HDL-C, apo A-I, apo A-IV, and apo C-III levels that are about 50% of normal (3). This condition is associated with aggressive, premature ASCVD. Additionally, there is evidence of mild fat malabsorption due to deficiency of apo A-IV. Patients with apo A-I/C-III deficiency have undetectable apo A-I and a similar lipid profile as those with apo A-I/C-III/A-IV deficiency (3). This condition is also associated with premature ASCVD. It is distinguished from the former by presence of planar xanthomas and absence of fat malabsorption (since apo A-IV is present). Familial apo A-I deficiency is itself a heterogeneous group of disorders associated with numerous Apo A-I mutations (3). Common manifestations include undetectable plasma Apo A-I, marked HDL deficiency with normal LDL-C and triglyceride levels, xanthomas (planar, tendon, and/or tubero-eruptive depending on the specific gene mutation), and premature ASCVD. Some forms of the disease are also associated with corneal manifestations, including corneal arcus and corneal opacification. One of the interesting manifestations of familial apo A-I deficiency is that levels of apo A-IV and apo E containing HDL particles are only modestly reduced, with preserved electrophoretic mobility and particle size (7).

It is notable that familial hypoalphalipoproteinemia is associated with an increased risk of premature ASCVD presumably due to the marked deficiency in Apo A-I and HDL. Given the increased ASCVD risk associated with Apo A-I deficiency, treatment is directed towards aggressive reduction of LDL-C and non-HDL-C levels and reducing other cardiovascular risk factors.

Some mutations in Apo A-I are associated with low HDL-C levels and hereditary amyloidosis and are the second most frequent cause of familial amyloidosis (6,8). Note that HDL-C levels are not always decreased in patients with familial amyloidosis secondary to Apo A-I mutations. The N-terminal fragment of the mutated protein is found in the amyloid fragments.

Tangier Disease

Tangier disease is due to mutations in the gene that codes for ATP-Binding Cassette transporter A1 (ABCA1) and is inherited in an autosomal co-dominant manner (9,10).  Fredrickson first reported this condition in two patients who hailed from Tangier Island in the Chesapeake Bay, for which the disorder is named. ABCA1 facilitates efflux of intracellular cholesterol from peripheral cells to lipid poor A1, the key first step of reverse cholesterol transport (11). As such, this disorder is characterized by severe deficiency of HDL-C (HDL-C <5 mg/dL) and the presence of only thepreß-1 HDL fraction of HDL (10). The poorly lipidated Apo A-I is rapidly catabolized by the kidney. These patients also demonstrate moderate hypertriglyceridemia and low LDL-C levels (10). The decrease in LDL-C is likely due to absence of the transfer of cholesterol from HDL to LDL. Studies have also suggested that an increase in LDL uptake by the liver also occurs (12). The increase in triglycerides may be due to the failure of HDL to provide co-factors that increase lipoprotein lipase activity. Additionally, ABCA1 deficiency in the liver increases triglyceride secretion and hepatic angiopoietin-like protein 3 secretion which could inhibit lipoprotein lipase activity leading to an increase in triglycerides (12,13).

Since ABCA1 deficiency impairs free cholesterol efflux from cells, there is accumulation of cholesterol esters in many tissues throughout the body (10). Classically, patients present with hepatosplenomegaly and enlarged yellow-orange hyperplastic tonsils, however, a wide spectrum of phenotypic manifestations is now appreciated with considerable variability in terms of clinical severity and organ involvement (9,10). Peripheral neuropathies are also a common complication and may be relapsing-remitting or chronic progressive (9,10). Tangier disease patients appear to have an increased risk of premature ASCVD, though not as pronounced as those with familial hypoalphalipoproteinemia (3,9,14). When the non-HDL-C levels are greater than 70mg/dL patients with Tangier disease are at higher risk of ASCVD whereas when the non-HDL-C levels are less than 70mg/dL ASCVD is low (9). Less common complications include corneal opacities and hematological manifestations such as thrombocytopenia and hemolytic anemia (9,10).

Individuals who are heterozygous for ABCA1 mutations have HDL-C levels that are variable but approximately 50% of normal with normal levels of preß-1 HDL but a deficiency of large α-1 and α-2 HDL particles (10). Cholesterol efflux capacity in heterozygotes has been reported as ~50% of normal. A mutation in one ABCA1 allele has been associated with increased risk of ASCVD in some studies and with no increase in ASCVD risk in other studies (15-20). Different mutations in ABCA1 result in varying HDL-C levels and phenotypes, which might explain the difference in ASCVD risk (21).

While Tangier patients manifest characteristically low HDL-C and Apo A-I, this lipid/lipoprotein phenotype is not adequate to make the diagnosis. ABCA1 gene sequence analysis is the preferred test to make the diagnosis of Tangier disease (10). Alternatively, non-denaturing two-dimensional electrophoresis followed by anti-apo A-I immunoblotting demonstrates only preβ1-HDL.

Currently, there is no specific treatment for Tangier disease (10). In fact, HDL-C raising therapies such as niacin and fibrates have proven ineffective in patients with this condition (22). Even HDL infusion was not beneficial (23). The major clinical issue in Tangier patients is disabling neuropathy; however, there is no effective intervention to manage this complication (10). Aggressive LDL-C lowering and treatment of other risk factors for atherosclerosis is recommended (10).

LCAT Deficiency  

LCAT is an enzyme that is bound primarily to HDL, with some also found on LDL (24,25). It facilitates cholesterol esterification by transferring a fatty acid from phosphatidyl choline to cholesterol (24,25). The hydrophobic cholesteryl esters are then sequestered in the core of the lipoprotein particles. LCAT is critical in the maturation of HDL particles. LCAT deficiency is an autosomal co-dominant disorder that manifests as either familial LCAT deficiency (FLD) or fish-eye disease in homozygotes (FED) (24,25). In FLD, mutations in LCAT lead to the inability of LCAT to esterify cholesterol in both HDL and LDL, whereas in FED, mutations in LCAT lead to the inability of LCAT to esterify cholesterol in HDL but the ability of LCAT to esterify cholesterol in LDL is preserved (24,25). Patients with FLD have virtually no cholesterol esters in the circulation while patients with FED have subnormal levels of cholesterol esters carried in apo B containing lipoproteins (24,25). Heterozygotes having decreases in HDL-C levels approximately midway between normal and homozygotes.  

Individuals with FLD develop corneal opacities (“fish eye”), normochromic hemolytic anemia (due to cholesterol enrichment of red blood cell membranes), mild thrombocytopenia, and proteinuric end stage renal disease, which is the major cause of morbidity and mortality (24,25). The corneal opacities begin early in life and some patients may need corneal transplants. The rate of development of renal disease is variable but in a large cohort renal failure occurred at a median age of 46 years (26). Patients with FED generally only manifest corneal opacities (24,25).

The lipid and lipoprotein profile in patients with FLD usually demonstrates low HDL-C levels (frequently <10 mg/dL) (24,27). In one cohort patients with FED tend to have higher HDL-C levels but in a large systematic review HDL-C levels were similar in patients with FLD and FED (24,27). LDL-C levels tend to be low in FLD and FED while triglyceride levels are increased (24,27). Lipoprotein X (Lp-X) particles are present in patients with FLD but not in patients with FED (24). Lp-X is a multilamellar vesicle with an aqueous core. It is primarily composed of free cholesterol and phospholipid with very little protein (albumin in the core and apolipoprotein C on the surface) and cholesteryl ester.

Given the association of Lp-X and kidney disease only with FLD (and not FED) and animal studies demonstrating the nephrotoxicity of Lp-X, it is likely that increased levels of Lp-X results in renal dysfunction in patients with FLD (25,28). Lp-X particles accumulate in the mesangial cells in the glomerulus and are thought to induce inflammation and breakdown of the basement membrane leading to proteinuria. It is notable that after renal transplantation in patients with FLD there is recurrence of renal damage in the transplanted kidney (26).

It is unclear as to whether LCAT deficiency is associated with an increased risk of ASCVD (25,29). Atherosclerosis imaging studies have yielded divergent data and the number of patients with FLD or FED studied is limited (25,29). In one study carriers of FLD mutations (i.e., heterozygotes) had a decrease in ASCVD while carriers of FED mutations had an increase in ASCVD (30). This may have been due to higher LDL-C levels in the carriers of FED mutations (30).

Current management of FLD focuses on managing the renal dysfunction. The associated kidney disease is traditionally managed with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and a low-fat diet (25). Whether lipid lowering drugs are beneficial is unknown. Possible future therapies include enzyme replacement therapy with recombinant human LCAT, liver-directed LCAT gene therapy, small peptide or molecule activators of LCAT, and HDL mimetics (31,32). Infusions of recombinant human LCAT has improved the anemia and most parameters of renal function in a patient with FLD (33). Administration of CER-001, an apolipoprotein A1 (apoA-1)–containing HDL mimetic, has been shown to have beneficial effects on kidney and eye disease in a patient with LCAT deficiency (34).  

Approach to the Patient with Low HDL-C Levels

When encountering a patient with very low HDL-C levels it is important to first determine if this is a new abnormality or has been present for a long time. If prior HDL-C levels are normal, this excludes a primary monogenic etiology. If the decrease in HDL-C is new, one should consider the possibility of very poorly controlled diabetes, inflammation, infections, malignancy, liver disease, paraproteinemia, anabolic steroids, or a paradoxical response to PPAR agonists. Marked hypertriglyceridemia can also lead to very low HDL-C levels. 

In a patient with long-standing very low HDL-C levels without an identifiable secondary cause, one should consider a monogenic etiology. To evaluate potential monogenic causes, a detailed family history, with attention to HDL-C levels, is important. Obtaining lipid levels from relatives is very helpful. A focused physical examination, with particular attention to the skin, eyes, tonsils, and spleen may point to a specific monogenic disorder. Plasma apo A-I levels should be obtained. Individuals with familial hypoalphalipoproteinemia deficiency have undetectable plasma apo A-I. Patients with Tangier disease demonstrate very low apo A-I levels (<5 mg/dL). LCAT deficiency is associated with apo A-I levels that are low but substantially higher than the other monogenic etiologies. Patients with LCAT deficiency also have a higher ratio of free: total cholesterol in plasma and measurement of plasma free (unesterified) cholesterol can be helpful. Two-dimensional gel electrophoresis of plasma followed by immunoblotting with antibodies specific for apo A-I separates lipid-poor preß-HDL from lipid-rich–HDL and can be helpful in differentiating these disorders. Genetic analysis is indicated when a monogenic disorder is suspected.

HIGH HDL-C CONDITIONS (HYPERALPHALIPOPROTEINEMIA)

An elevated concentration of apo A-I and apo A-II is called hyperalphalipoproteinemia (HALP). HALP is classified as moderate (HDL-C levels between 80 and 100 mg/dL) or severe (HDL-C levels > 100 mg/dL). While it is well recognized that high HDL-C levels are associated with a decrease in ASCVD it should be noted that very high HDL-C levels are paradoxically associated with an increase in ASCVD (35,36).

HALP is a heterogeneous condition caused by a variety of genetic and secondary conditions (for example ethanol abuse, primary biliary cirrhosis, multiple lipomatosis, emphysema, exercise, and certain drugs such as estrogens). In many individuals, the very high HDL-C levels have a polygenic origin (5,37). Given the focus of this chapter, monogenic causes of HALP will be reviewed. Monogenic HALP includes CETP deficiency, hepatic lipase deficiency, endothelial lipase deficiency, and loss of function mutations in SRB1. Despite epidemiology that demonstrates an inverse relationship between HDL-C and ASCVD risk, some forms of familial HALP are paradoxically associated with increased cardiovascular risk.

HALP is generally identified incidentally after routine assessment of a lipid profile as it is not usually associated with any signs or symptoms. Generally, patients are asymptomatic and no medical therapy is required.

Cholesterol Ester Transfer Protein (CETP) Deficiency

CETP transfers cholesteryl esters from HDL particles to triglyceride rich lipoproteins and LDL in exchange for triglycerides (11). Individuals who are homozygous for CETP variants have very high HDL-C levels (>100mg/dL) while heterozygotes have moderately increased HDL-C levels (38-41). LDL-C and apo B levels may be normal or modestly decreased. The increase in HDL cholesterol are largely due to the accumulation of cholesterol esters (39). The decrease in LDL-C is due to the failure of cholesterol ester transport from HDL to apo B containing lipoproteins. There is a predominance of small LDL particles. Individuals who are heterozygotes for CETP mutations show modestly elevated HDL-C levels (38,39). In Japanese individuals with HDL-C levels > 100mg/dL 67% were demonstrated to have CETP gene mutations (42). CETP deficiency is the most important and frequent cause of HALP in Japan. CETP deficiency is common in other Asian populations but is relatively rare in other ethnic groups (39). Despite extensive studies the effect of CETP variants on the risk of ASCVD is uncertain (38-40,43). A variety of studies have indicated that a decrease in LDL-C and non-HDL-C levels (i.e. pro-atherogenic lipoproteins) rather than an increase in HDL-C induced by CETP variants underlies a potential beneficial effect on ASCVD (44).  

Endothelial Lipase (EL) Deficiency

Endothelial lipase (EL) is encoded by the LIPG gene and hydrolyzes phospholipids on HDL resulting in smaller HDL particles that are more rapidly metabolized (11). Genetic variants in LIPG have been identified Iin individuals with elevated HDL-C levels (38,39). As one would predict large HDL particles enriched in phospholipids are observed in individuals deficient in EL (39). Whether variants in LIPG leading to decreased EL activity and increased HDL-C levels reduces ASCVD risk is uncertain (38-40).

Hepatic Lipase (HL) Deficiency

Hepatic lipase (HL) is encoded by the LIPC gene and mediates the hydrolysis of triglycerides and phospholipids in intermediate density lipoproteins (IDL) and LDL leading to smaller particles (IDL is converted to LDL; LDL is converted from large LDL to small LDL) (11). It also mediates the hydrolysis of triglycerides and phospholipids in HDL resulting in smaller HDL particles (11). Several case reports of families with elevated HDL-C levels (HALP) caused by a genetically defined HL deficiency have been described (39,40). HL deficiency may also be associated with elevated triglycerides and cholesterol with increased intermediate density lipoproteins (IDL) (40,45). Several HL deficient individuals had premature ASCVD likely due to increased levels of apo B containing lipoproteins (40,45). Heterozygotes do not appear to have discrete lipoprotein abnormalities (45).

Scavenger Receptor Class B Type I (SR-BI)

Scavenger receptor class B type I (SR-BI) is encoded by the SCARB1 gene and facilitates the selective uptake of the cholesterol esters from HDL into the liver, adrenal, ovary, and testes (11). In macrophages and other cells, SR-B1 facilitates the efflux of cholesterol from the cell to HDL particles (11). SR-B1 deficient mice have an increase in atherosclerosis despite elevated HDL-C levels (46). Mutations in SCARB1 associated with decreased SR-B1 have been observed in individuals with high HDL-C levels (47-49). Heterozygotes have intermediate elevations of HDL-C between wild-type and homozygous individuals. Studies have suggested that some but not all mutations in SCARB1 result in an increased risk of ASCVD despite increased HDL-C levels (40,49). A decrease in adrenal function has been reported in some individuals with SCARB1 mutations likely due to a reduced ability of SR-B1 to facilitate cholesterol uptake into the adrenal glands (48,50). Abnormalities in platelet function have also been observed in some patients (50).

ACKNOWLEDGEMENTS

This work was supported by grants from the Northern California Institute for Research and Education.

REFERENCES

1. Kjeldsen EW, Thomassen JQ, Frikke-Schmidt R. HDL cholesterol concentrations and risk of atherosclerotic cardiovascular disease - Insights from randomized clinical trials and human genetics. Biochim Biophys Acta Mol Cell Biol Lipids 2021; 1867:159063
2. Feingold KR. Obesity and Dyslipidemia. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, Dungan K, Grossman A, Hershman JM, Hofland J, Kalra S, Kaltsas G, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrere B, McGee EA, McLachlan R, Morley JE, New M, Purnell J, Sahay R, Singer F, Stratakis CA, Trence DL, Wilson DP, eds. Endotext. South Dartmouth (MA) 2023.
3. Schaefer EJ, Anthanont P, Diffenderfer MR, Polisecki E, Asztalos BF. Diagnosis and treatment of high density lipoprotein deficiency. Prog Cardiovasc Dis 2016; 59:97-106
4. Geller AS, Polisecki EY, Diffenderfer MR, Asztalos BF, Karathanasis SK, Hegele RA, Schaefer EJ. Genetic and secondary causes of severe HDL deficiency and cardiovascular disease. J Lipid Res 2018; 59:2421-2435
5. Dron JS, Wang J, Low-Kam C, Khetarpal SA, Robinson JF, McIntyre AD, Ban MR, Cao H, Rhainds D, Dube MP, Rader DJ, Lettre G, Tardif JC, Hegele RA. Polygenic determinants in extremes of high-density lipoprotein cholesterol. J Lipid Res 2017; 58:2162-2170
6. Zanoni P, von Eckardstein A. Inborn errors of apolipoprotein A-I metabolism: implications for disease, research and development. Curr Opin Lipidol 2020; 31:62-70
7. Santos RD, Schaefer EJ, Asztalos BF, Polisecki E, Wang J, Hegele RA, Martinez LR, Miname MH, Rochitte CE, Da Luz PL, Maranhao RC. Characterization of high density lipoprotein particles in familial apolipoprotein A-I deficiency. J Lipid Res 2008; 49:349-357
8. Joy T, Wang J, Hahn A, Hegele RA. APOA1 related amyloidosis: a case report and literature review. Clin Biochem 2003; 36:641-645
9. Hooper AJ, Hegele RA, Burnett JR. Tangier disease: update for 2020. Curr Opin Lipidol 2020; 31:80-84
10. Burnett JR, Hooper AJ, McCormick SPA, Hegele RA. Tangier Disease. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, Amemiya A, eds. GeneReviews((R)). Seattle (WA) 2019.
11. Feingold KR. Introduction to Lipids and Lipoproteins. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, Dungan K, Grossman A, Hershman JM, Hofland J, Kalra S, Kaltsas G, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrere B, McGee EA, McLachlan R, Morley JE, New M, Purnell J, Sahay R, Singer F, Stratakis CA, Trence DL, Wilson DP, eds. Endotext. South Dartmouth (MA) 2021.
12. Liu M, Chung S, Shelness GS, Parks JS. Hepatic ABCA1 and VLDL triglyceride production. Biochim Biophys Acta 2012; 1821:770-777
13. Bi X, Pashos EE, Cuchel M, Lyssenko NN, Hernandez M, Picataggi A, McParland J, Yang W, Liu Y, Yan R, Yu C, DerOhannessian SL, Phillips MC, Morrisey EE, Duncan SA, Rader DJ. ATP-Binding Cassette Transporter A1 Deficiency in Human Induced Pluripotent Stem Cell-Derived Hepatocytes Abrogates HDL Biogenesis and Enhances Triglyceride Secretion. EBioMedicine 2017; 18:139-145
14. Koseki M, Yamashita S, Ogura M, Ishigaki Y, Ono K, Tsukamoto K, Hori M, Matsuki K, Yokoyama S, Harada-Shiba M. Current Diagnosis and Management of Tangier Disease. J Atheroscler Thromb 2021; 28:802-810
15. Bochem AE, van Wijk DF, Holleboom AG, Duivenvoorden R, Motazacker MM, Dallinga-Thie GM, de Groot E, Kastelein JJ, Nederveen AJ, Hovingh GK, Stroes ES. ABCA1 mutation carriers with low high-density lipoprotein cholesterol are characterized by a larger atherosclerotic burden. Eur Heart J 2013; 34:286-291
16. van Dam MJ, de Groot E, Clee SM, Hovingh GK, Roelants R, Brooks-Wilson A, Zwinderman AH, Smit AJ, Smelt AH, Groen AK, Hayden MR, Kastelein JJ. Association between increased arterial-wall thickness and impairment in ABCA1-driven cholesterol efflux: an observational study. Lancet 2002; 359:37-42
17. Schaefer EJ, Zech LA, Schwartz DE, Brewer HB, Jr. Coronary heart disease prevalence and other clinical features in familial high-density lipoprotein deficiency (Tangier disease). Ann Intern Med 1980; 93:261-266
18. Frikke-Schmidt R, Nordestgaard BG, Stene MC, Sethi AA, Remaley AT, Schnohr P, Grande P, Tybjaerg-Hansen A. Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease. JAMA 2008; 299:2524-2532
19. Frikke-Schmidt R. Genetic variation in the ABCA1 gene, HDL cholesterol, and risk of ischemic heart disease in the general population. Atherosclerosis 2010; 208:305-316
20. Iatan I, Alrasadi K, Ruel I, Alwaili K, Genest J. Effect of ABCA1 mutations on risk for myocardial infarction. Curr Atheroscler Rep 2008; 10:413-426
21. Brunham LR, Singaraja RR, Hayden MR. Variations on a gene: rare and common variants in ABCA1 and their impact on HDL cholesterol levels and atherosclerosis. Annu Rev Nutr 2006; 26:105-129
22. Serfaty-Lacrosniere C, Civeira F, Lanzberg A, Isaia P, Berg J, Janus ED, Smith MP, Jr., Pritchard PH, Frohlich J, Lees RS, et al. Homozygous Tangier disease and cardiovascular disease. Atherosclerosis 1994; 107:85-98
23. Schaefer EJ, Anderson DW, Zech LA, Lindgren FT, Bronzert TB, Rubalcaba EA, Brewer HB, Jr. Metabolism of high density lipoprotein subfractions and constituents in Tangier disease following the infusion of high density lipoproteins. J Lipid Res 1981; 22:217-228
24. Pavanello C, Calabresi L. Genetic, biochemical, and clinical features of LCAT deficiency: update for 2020. Curr Opin Lipidol 2020; 31:232-237
25. Saeedi R, Li M, Frohlich J. A review on lecithin:cholesterol acyltransferase deficiency. Clin Biochem 2015; 48:472-475
26. Pavanello C, Ossoli A, Arca M, D'Erasmo L, Boscutti G, Gesualdo L, Lucchi T, Sampietro T, Veglia F, Calabresi L. Progression of chronic kidney disease in familial LCAT deficiency: a follow-up of the Italian cohort. J Lipid Res2020; 61:1784-1788
27. Mehta R, Elias-Lopez D, Martagon AJ, Perez-Mendez OA, Sanchez MLO, Segura Y, Tusie MT, Aguilar-Salinas CA. LCAT deficiency: a systematic review with the clinical and genetic description of Mexican kindred. Lipids Health Dis 2021; 20:70
28. Ossoli A, Neufeld EB, Thacker SG, Vaisman B, Pryor M, Freeman LA, Brantner CA, Baranova I, Francone NO, Demosky SJ, Jr., Vitali C, Locatelli M, Abbate M, Zoja C, Franceschini G, Calabresi L, Remaley AT. Lipoprotein X Causes Renal Disease in LCAT Deficiency. PLoS One 2016; 11:e0150083
29. Norum KR, Remaley AT, Miettinen HE, Strom EH, Balbo BEP, Sampaio C, Wiig I, Kuivenhoven JA, Calabresi L, Tesmer JJ, Zhou M, Ng DS, Skeie B, Karathanasis SK, Manthei KA, Retterstol K. Lecithin:cholesterol acyltransferase: symposium on 50 years of biomedical research from its discovery to latest findings. J Lipid Res2020; 61:1142-1149
30. Oldoni F, Baldassarre D, Castelnuovo S, Ossoli A, Amato M, van Capelleveen J, Hovingh GK, De Groot E, Bochem A, Simonelli S, Barbieri S, Veglia F, Franceschini G, Kuivenhoven JA, Holleboom AG, Calabresi L. Complete and Partial Lecithin:Cholesterol Acyltransferase Deficiency Is Differentially Associated With Atherosclerosis. Circulation 2018; 138:1000-1007
31. Freeman LA, Karathanasis SK, Remaley AT. Novel lecithin: cholesterol acyltransferase-based therapeutic approaches. Curr Opin Lipidol 2020; 31:71-79
32. Vitali C, Rader DJ, Cuchel M. Novel therapeutic opportunities for familial lecithin:cholesterol acyltransferase deficiency: promises and challenges. Curr Opin Lipidol 2023; 34:35-43
33. Shamburek RD, Bakker-Arkema R, Auerbach BJ, Krause BR, Homan R, Amar MJ, Freeman LA, Remaley AT. Familial lecithin:cholesterol acyltransferase deficiency: First-in-human treatment with enzyme replacement. J Clin Lipidol 2016; 10:356-367
34. Faguer S, Colombat M, Chauveau D, Bernadet-Monrozies P, Beq A, Delas A, Soler V, Labadens I, Huart A, Benlian P, Schanstra JP. Administration of the High-Density Lipoprotein Mimetic CER-001 for Inherited Lecithin-Cholesterol Acyltransferase Deficiency. Ann Intern Med 2021; 174:1022-1025
35. Hirata A, Sugiyama D, Watanabe M, Tamakoshi A, Iso H, Kotani K, Kiyama M, Yamada M, Ishikawa S, Murakami Y, Miura K, Ueshima H, Okamura T, Evidence for Cardiovascular Prevention from Observational Cohorts in Japan Research G. Association of extremely high levels of high-density lipoprotein cholesterol with cardiovascular mortality in a pooled analysis of 9 cohort studies including 43,407 individuals: The EPOCH-JAPAN study. J Clin Lipidol 2018; 12:674-684 e675
36. Madsen CM, Varbo A, Nordestgaard BG. Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: two prospective cohort studies. Eur Heart J 2017; 38:2478-2486
37. Motazacker MM, Peter J, Treskes M, Shoulders CC, Kuivenhoven JA, Hovingh GK. Evidence of a polygenic origin of extreme high-density lipoprotein cholesterol levels. Arterioscler Thromb Vasc Biol 2013; 33:1521-1528
38. Larach DB, Cuchel M, Rader DJ. Monogenic causes of elevated HDL cholesterol and implications for development of new therapeutics. Clin Lipidol 2013; 8:635-648
39. Giammanco A, Noto D, Barbagallo CM, Nardi E, Caldarella R, Ciaccio M, Averna MR, Cefalu AB. Hyperalphalipoproteinemia and Beyond: The Role of HDL in Cardiovascular Diseases. Life (Basel) 2021; 11
40. Kardassis D, Thymiakou E, Chroni A. Genetics and regulation of HDL metabolism. Biochim Biophys Acta Mol Cell Biol Lipids 2021; 1867:159060
41. Yamashita S, Maruyama T, Hirano K, Sakai N, Nakajima N, Matsuzawa Y. Molecular mechanisms, lipoprotein abnormalities and atherogenicity of hyperalphalipoproteinemia. Atherosclerosis 2000; 152:271-285
42. Hirano K, Yamashita S, Kuga Y, Sakai N, Nozaki S, Kihara S, Arai T, Yanagi K, Takami S, Menju M, et al. Atherosclerotic disease in marked hyperalphalipoproteinemia. Combined reduction of cholesteryl ester transfer protein and hepatic triglyceride lipase. Arterioscler Thromb Vasc Biol 1995; 15:1849-1856
43. Yamashita S, Matsuzawa Y. Re-evaluation of cholesteryl ester transfer protein function in atherosclerosis based upon genetics and pharmacological manipulation. Curr Opin Lipidol 2016; 27:459-472
44. Nicholls SJ, Ray KK, Nelson AJ, Kastelein JJP. Can we revive CETP-inhibitors for the prevention of cardiovascular disease? Curr Opin Lipidol 2022; 33:319-325
45. Weissglas-Volkov D, Pajukanta P. Genetic causes of high and low serum HDL-cholesterol. J Lipid Res 2010; 51:2032-2057
46. Trigatti B, Rayburn H, Vinals M, Braun A, Miettinen H, Penman M, Hertz M, Schrenzel M, Amigo L, Rigotti A, Krieger M. Influence of the high density lipoprotein receptor SR-BI on reproductive and cardiovascular pathophysiology. Proc Natl Acad Sci U S A 1999; 96:9322-9327
47. Brunham LR, Tietjen I, Bochem AE, Singaraja RR, Franchini PL, Radomski C, Mattice M, Legendre A, Hovingh GK, Kastelein JJ, Hayden MR. Novel mutations in scavenger receptor BI associated with high HDL cholesterol in humans. Clin Genet 2011; 79:575-581
48. Vergeer M, Korporaal SJ, Franssen R, Meurs I, Out R, Hovingh GK, Hoekstra M, Sierts JA, Dallinga-Thie GM, Motazacker MM, Holleboom AG, Van Berkel TJ, Kastelein JJ, Van Eck M, Kuivenhoven JA. Genetic variant of the scavenger receptor BI in humans. N Engl J Med 2011; 364:136-145
49. Zanoni P, Khetarpal SA, Larach DB, Hancock-Cerutti WF, Millar JS, Cuchel M, DerOhannessian S, Kontush A, Surendran P, Saleheen D, Trompet S, Jukema JW, De Craen A, Deloukas P, Sattar N, Ford I, Packard C, Majumder A, Alam DS, Di Angelantonio E, Abecasis G, Chowdhury R, Erdmann J, Nordestgaard BG, Nielsen SF, Tybjaerg-Hansen A, Schmidt RF, Kuulasmaa K, Liu DJ, Perola M, Blankenberg S, Salomaa V, Mannisto S, Amouyel P, Arveiler D, Ferrieres J, Muller-Nurasyid M, Ferrario M, Kee F, Willer CJ, Samani N, Schunkert H, Butterworth AS, Howson JM, Peloso GM, Stitziel NO, Danesh J, Kathiresan S, Rader DJ, Consortium CHDE, Consortium CAE, Global Lipids Genetics C. Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. Science 2016; 351:1166-1171
50. Chadwick AC, Sahoo D. Functional genomics of the human high-density lipoprotein receptor scavenger receptor BI: an old dog with new tricks. Curr Opin Endocrinol Diabetes Obes 2013; 20:124-131