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Feingold KR, Anawalt B, Blackman MR, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-.

Introduction to Lipids and Lipoproteins

Kenneth R. Feingold, MD
Emeritus Professor of Medicine, University of California- San Francisco
Email: [email protected]
Corresponding author.

Last Update: January 14, 2024.

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. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text,
WWW.ENDOTEXT.ORG.

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)
Lipoproteins are complex particles that have a central hydrophobic core of non-polar lipids, primarily cholesterol
esters and triglycerides. This hydrophobic core is surrounded by a hydrophilic membrane consisting of phospholipids,
free cholesterol, and apolipoproteins (Figure 1). Plasma lipoproteins are divided into seven classes based on size, lipid
composition, and apolipoproteins (Table 1 and Figure 2).

Figure 1.

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

Table 1.

Lipoprotein Classes

Lipoprotein Density Size Major Lipids Major Apoproteins

(g/ml) (nm)
Chylomicrons <0.930 75-1200 Triglycerides Apo B-48, Apo C, Apo E, Apo A-I, A-II,
A-IV
Chylomicron 0.930- 1.006 30-80 Triglycerides Apo B-48, Apo E
Remnants Cholesterol
VLDL 0.930- 1.006 30-80 Triglycerides Apo B-100, Apo E, Apo C
IDL 1.006- 1.019 25-35 Triglycerides Apo B-100, Apo E, Apo C
Cholesterol
Lipoprotein Density Size Major Lipids Major Apoproteins
(g/ml) (nm)
LDL 1.019- 1.063 18- 25 Cholesterol Apo B-100
HDL 1.063- 1.210 5- 12 Cholesterol Apo A-I, Apo A-II, Apo C, Apo E
Phospholipids
Lp (a) 1.055- 1.085 ~30 Cholesterol Apo B-100, Apo (a)

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).

Table 2.

Classification of HDL

Method of classification Types of HDL

Density gradient ultracentrifugation HDL2, HDL3, very high-density HDL
Nuclear magnetic resonance large, medium, and small
Method of classification Types of HDL
Gradient gel electrophoresis HDL 2a, 2b, 3a, 3b, 3c
2-dimensional gel electrophoresis pre-beta 1 and 2, alpha 1, 2, 3, 4
Apolipoprotein composition A-I particles, A-I: A-II particles, A-I: E particles

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.

Table 3.

Apolipoproteins

Apolipoprotein MW Primary Lipoprotein Association Function

Source
Apo A-I 28,000 Liver, HDL, chylomicrons Structural protein for HDL, Activates
Intestine LCAT
Apolipoprotein MW Primary Lipoprotein Association Function
Source
Apo A-II 17,000 Liver HDL, chylomicrons Structural protein for HDL, Activates
hepatic lipase
Apo A-IV 45,000 Intestine HDL, chylomicrons Unknown
Apo A-V 39,000 Liver VLDL, chylomicrons, HDL Promotes LPL mediated TG lipolysis
Apo B-48 241,000 Intestine Chylomicrons Structural protein for chylomicrons
Apo B-100 512,000 Liver VLDL, IDL, LDL, Lp (a) Structural protein, Ligand for LDL
receptor
Apo C-I 6,600 Liver Chylomicrons, VLDL, Activates LCAT
HDL
Apo C-II 8,800 Liver Chylomicrons, VLDL, Co-factor for LPL
HDL
Apo C-III 8,800 Liver Chylomicrons, VLDL, Inhibits LPL and uptake of lipoproteins
HDL
Apo E 34,000 Liver Chylomicron remnants, Ligand for LDL receptor
IDL, HDL
Apo (a) 250,000- Liver Lp (a) Inhibits plasminogen activation
800,00

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.

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