Dyslipidemia (Lipoprotein classification, metabolism, and role in atherosclerosis)
INTRODUCTION
1.
2.
Lipids (such as cholesterol and TG) are insoluble in plasma and circulating lipid is carried in
lipoproteins that transport lipid to various tissues for energy utilization, lipid deposition,
steroid hormone production, and bile acid formation. The lipoprotein consists of esterified
and unesterified cholesterol, TGs, and phospholipids, and protein. The protein components of
lipoprotein are known as apolipoproteins (apo) or apoproteins. The different apolipoproteins
serve as cofactors for enzymes and ligands for receptors.
The classification of lipoproteins, function of different apolipoproteins that they contain,
pathways of lipid metabolism, and how lipoprotein disorders can promote development of
atherosclerosis will be reviewed here.
CLASSIFICATION
1. Chylomicrons
A. Chylomicrons are very large particles that carry dietary lipid. They are associated with
variety of apolipoproteins, including A-I, A-II, A-IV, B-48, C-I, C-II, C-III, and E.
2. Very low density lipoprotein (VLDL)
A. VLDL carries endogenous TG and to lesser degree cholesterol. The major
apolipoproteins associated with VLDL are B-100, C-I, C-II, C-III, and E.
3. Intermediate density lipoprotein (IDL)
A. IDL carries CE and TG. It is associated with apo B-100, C-III, and E.
4. Low density lipoprotein (LDL)
5.
6.
A. LDL carries CE and is associated with apo B-100 and C-III.
High density lipoprotein (HDL)
A. HDL also carries CE. It is associated with apo A-I, A-II, C-I, C-II, C-III, D, and E.
Apolipoproteins
A. Understanding major functions of different apolipoproteins is important clinically,
because defects in apolipoprotein metabolism lead to abnormalities in lipid handling.
(See appropriate topic reviews on disorders of LDL-c, HDL-c, TG, and Lp (a) metabolism).
B. The assembly and secretion of apo B containing lipoproteins in liver and intestines is
dependent upon microsomal TG transfer protein which transfers lipids to apo B. In one
study, apo B and microsomal transfer protein genes expressed in human heart, strongly
C.
D.
E.
F.
suggesting that heart synthesizes and secretes apo B containing lipoproteins. This may
represent a pathway of "reverse TG transport" by which cardiac myocytes can unload
surplus fatty acids not required for fuel.
A-I — Structural protein for HDL; activator of lecithin-cholesterol acyltransferase.
A-II — Structural protein for HDL; activator of hepatic lipase.
A-IV — Activator of LPL and LCAT.
B-100 — Structural protein for VLDL, IDL, LDL, and Lp (a); ligand for LDL receptor;
required for assembly and secretion of VLDL.
G.
B-48 — Contains 48% of B-100; required for assembly and secretion of chylomicrons;
does not bind to LDL receptor.
H.
I.
J.
C-I — Activator of LCAT.
C-II — Essential cofactor for LPL.
C-III — Interferes with apo-E mediated clearance of TG-enriched lipoproteins by cellular
receptors, particularly in liver; inhibits TG hydrolysis by lipoprotein lipase and hepatic
lipase; has multiple proatherogenic effects on arterial wall, including interfering with
normal endothelial function.
D — May be cofactor for cholesteryl ester transfer protein (CETP).
E — Ligand for hepatic chylomicron and VLDL remnant receptor, leading to clearance of
these lipoproteins from circulation; ligand for LDL receptor. There are 3 different apo E
K.
L.
alleles in humans: E2, which has cysteine residues at positions 112 and 158; E3, which
occurs in 60 to 80% of Caucasians and has cysteine at position 112 and arginine at
position 158; and E4, which has arginine residues at positions 112 and 158. These alleles
encode for combination of apo E isoforms that are inherited in co-dominant fashion.
Compared to apo E3, apo E2 has reduced affinity and apo E4 has enhanced affinity for
LDL (apo B/E) receptor. These isoforms are important clinically because apo E2 is
associated with familial dysbetalipoproteinemia (due to less efficient clearance of VLDL
and chylomicrons) and apo E4 is associated with increased risk of hypercholesterolemia
and CAD.
M. Apo (a) — Structural protein for Lp (a); inhibitor of plasminogen activation on Lp (a).
CLINICAL CLASSIFICATION OF DYSLIPIDEMIAS
1. The major classes of dyslipidemia are classified according to the Fredrickson phenotype. A
variety of defects, some of which are familial, can produce these disorders.
2. Fredrickson phenotype I — serum chylomicrons elevated; TG are elevated to > 99th
percentile
3. Fredrickson phenotype IIa — serum LDL-c elevated; the total cholesterol is > 90th percentile.
Concentrations of TG and/or apo B may also be ≥ 90th percentile.
4. Fredrickson phenotype IIb — serum LDL and VLDL-c elevated; total cholesterol and/or TG
may be ≥ 90th percentile and apo B ≥ 90th percentile.
5. Fredrickson phenotype III — serum VLDL remnants and chylomicrons elevated; total
6.
7.
cholesterol and TG > 90th percentile
Fredrickson phenotype IV — serum VLDL elevated; total cholesterol may be > 90th percentile
and may also see TG > 90th percentile or low HDL
Fredrickson phenotype V — elevated serum chylomicrons and VLDL; TG > 99th percentile.
EXOGENOUS PATHWAY OF LIPID METABOLISM
1. Lipoprotein metabolism can be divided into exogenous and endogenous pathways. The
exogenous pathway starts with intestinal absorption of dietary cholesterol and fatty acids.
The mechanisms regulating amount of dietary cholesterol that is absorbed are unknown.
Sitosterolemia is rare AR disorder associated with hyperabsorption of cholesterol and plant
sterols from intestine. These genes involved are expressed primarily in liver and intestine and
are upregulated by cholesterol feeding; they may normally cooperate to limit intestinal sterol
absorption.
2.
3.
Within intestinal cell, FFA combine with glycerol to form TG, and cholesterol is esterified by
ACAT to form CE. The important role of ACAT was established in animal model of ACAT
deficiency, which found complete resistance to diet-induced hypercholesterolemia due to
lack of CE synthesis and reduced capacity to absorb cholesterol. Despite this, clinical trials
have found that ACAT inhibitors may worsen atherosclerosis. TG and cholesterol are
assembled intracellularly as chylomicrons. The main apolipoprotein is B-48, but C-II and E are
acquired as chylomicrons enter circulation. Apo B-48 permits lipid binding to chylomicron but
not does not bind to LDL receptor, thereby preventing premature clearance of chylomicrons
from circulation before they are acted upon by LPL.
Apo C-II is cofactor for LPL which makes chylomicrons progressively smaller primarily by
hydrolyzing core TG and releasing FFA. FFA are then used as energy source, converted to TG,
or stored in adipose tissue. The end-products of chylomicron metabolism are chylomicron
remnants that are cleared from circulation by hepatic chylomicron remnant receptors for
which apo E is high-affinity ligand. The chylomicron remnants contain smaller core of lipids
that is enveloped by excess surface components. These surface constituents are transferred
from chylomicron remnant for formation of HDL.
ENDOGENOUS PATHWAY OF LIPID METABOLISM
1. The endogenous pathway of lipid metabolism begins with synthesis of VLDL by liver. VLDL
particles contain core of TG (60% by mass) and CE (20% by mass). Microsomal triglyceride
transfer protein (MTP) is intracellular lipid-transfer protein found in ER. It is essential for
transfer of lipid molecules (principally TG) onto apo B 100 in liver. The surface
apolipoproteins for VLDL are noted above. They include apo C-II which acts as cofactor for LPL,
apo C-III which inhibits this enzyme, and apo B-100 and E which serve as ligands for apo B/E
(LDL) receptor. In absence of functional MTP, VLDL is not secreted into circulation.
Abetalipoproteinemia is rare genetic disorder in which MTP is absent.
2.
3.
4.
The TG core of nascent VLDL particles is hydrolyzed by LPL. During lipolysis, core of VLDL
particle is reduced, generating VLDL remnant particles (also called IDL) that are depleted of
TG via process similar to generation of chylomicron remnants. Some of excess surface
components in remnant particle, including phospholipid, unesterified cholesterol, and apo A,
C and E, are transferred to HDL.
VLDL remnants can either be cleared from circulation by apo B/E (LDL) or remnant receptors
or remodeled by hepatic lipase to form LDL particles. There are four common sequence
polymorphisms in hepatic lipase gene promoter; the most frequent is C to T substitution. The
presence of C allele is associated with higher hepatic lipase activity; smaller, denser, and
more atherogenic LDL particles, and inversely with lower levels of HDL-c.
Low density lipoprotein (LDL)
A. LDL particles contain core of CE, lesser amounts of TG, and are enriched in apo B-100,
which is ligand for binding to apo B/E (LDL) receptor. LDL can be internalized by hepatic
and nonhepatic tissues. Hepatic LDL-c can be converted to bile acids and secreted into
intestinal lumen. LDL-c internalized by nonhepatic tissues can be used for hormone
production, cell membrane synthesis, or stored in esterified form.
B.
C.
Internalization of LDL is regulated by cellular cholesterol requirements via negative
feedback control of apo B/E (LDL) receptor expression. Cells in positive cholesterol
balance, for example, suppress apo B/E (LDL) receptor expression. On the other hand,
decreased activity of HMG CoA reductase, enzyme that controls rate of de novo
cholesterol synthesis by cell, leads sequentially to fall in cell cholesterol, increased
expression of apo B/E (LDL) receptors, enhanced uptake of cholesterol from circulation,
and reduction in plasma cholesterol concentration.
Circulating LDL can also enter macrophages and some other tissues through unregulated
scavenger receptor. This pathway can result in excess accumulation of intracellular
cholesterol and formation of foam cells which contribute to formation of atheromatous
plaques.
D.
5.
The importance of LDL receptor in regulation of cholesterol metabolism has been
demonstrated in both experimental animals and humans. Knockout of LDL receptor in
transgenic mice leads to substantial elevation in total cholesterol levels, defect that can
be reversed by restoring LDL receptor gene. In humans, familial hypercholesterolemia is
often associated with defect in LDL receptor.
High density lipoprotein (HDL)
A. The formation and metabolism of HDL involves the following steps.
i.
Hepatic and intestinal synthesis of small nascent HDL particles composed of
phospholipid and apolipoproteins.
ii.
Procurement of surface components (phospholipids, cholesterol, and
iii.
apolipoproteins) from TG-depleted chylomicron and VLDL remnants.
Acquisition of free cholesterol from tissue and other lipoproteins, as initial HDL
particles contain relatively little cholesterol. Apo A-I on surface of HDL plays central
role in this process. It serves as signal transduction protein to mobilize CE from
intracellular pools. After diffusion of free cholesterol onto HDL, cholesterol is
esterified to CE by LCAT, plasma enzyme that is activated primarily by apo A-I. By
similar mechanism, HDL can act as acceptor for cholesterol released during lipolysis
of TG-containing lipoproteins.
B.
6.
Cholesterol efflux regulatory protein also appears to play important role in uptake of
cellular cholesterol by HDL by promoting transfer of intracellular cholesterol to cell
membrane. Mutations in gene encoding for this protein, ABC1, are associated with low
serum HDL in familial HDL deficiency and Tangier disease.
C. Lipid transfer proteins, such as CETP, facilitate movement of these newly synthesized CE
to apo B-containing lipoproteins (VLDL, IDL, and LDL). The cholesterol can then be
delivered to tissues for steroid synthesis or storage.
D. The net effect of last two steps is removal of excess cholesterol from cells, which
constitutes most of anti-atherogenic effect of HDL.
Lipoprotein (a)
A. Lp (a) is specialized form of LDL that is assembled extracellularly from apo (a) and LDL.
Apo (a) linked to apo B-100 on the surface of LDL by disulfide bridges. The formation of
apo (a): apo B complexes require an LDL particle of certain morphology and composition.
The structural integrity of LDL, and therefore Lp (a) formation, are modulated by LCAT.
The apo (a) chain contains 5 domains known as kringles. The 4th kringle contains regions
that are homologous with fibrin-binding domains of plasminogen. Through this
structural similarity to plasminogen, Lp (a) interferes with fibrinolysis by competing with
plasminogen binding to plasminogen receptors, fibrinogen, and fibrin.
B.
The net effect is impaired plasminogen activation and plasmin generation at thrombus
surface, leading to decreased thrombolysis. Lp (a) can also bind to macrophages via
high-affinity receptor, possibly promoting foam cell formation and localization of Lp (a)
at atherosclerotic plaques. The full discussion of potential role of Lp (a) in development
of atherosclerosis is found elsewhere.
LIPOPROTEINS AND ATHEROSCLEROSIS
1. Abnormal lipoprotein metabolism is major predisposing factor to atherosclerosis.
2. It is estimated, for example, that dyslipidemia is present in over 70% of patients with
premature CAD. Although individual disorders are discussed elsewhere, it is useful to review
briefly how high levels of LDL-c, Lp (a), or TG or low levels of HDL-c might promote atheroma
formation.
3.
Low density lipoprotein (LDL)
A. LDL particles contain TC, TG, phospholipids, and apo B-100 and C-III. All LDL particles
contain apo B-100, whereas 10 to 20% of LDL particles contain apo C-III. Thus, there is a
direct relationship between apo B-100 and LDL levels.
B. Elevated plasma apo B-100 containing lipoproteins can induce development of
atherosclerosis even in absence of other risk factors. It has been proposed that initiating
event in atherogenesis is subendothelial retention of apo B-100 containing lipoproteins
via charge-mediated interaction with proteoglycans in ECM. Consistent with this
hypothesis is observation that mice expressing LDL with defective proteoglycan binding
develop significantly less atherosclerosis than mice expressing wild-type LDL.
C.
D.
Small LDL particles penetrate endothelial barrier 1.7-fold more than large LDL particles;
these electronegative small LDL particles interact with positively charged intimal
proteoglycans. The increased retention of small LDL particles in vessel wall allows longer
time for reactive oxygen species modification of surface phospholipids and unesterified
cholesterol. In addition, small LDL phenotype is associated with clustering of other risk
factors, including elevated levels of TG, VLDL, and IDL, reduced concentrations of HDL
and HDL2, and insulin resistance. The discussion of clinical use of measurement of LDL
particle size is found elsewhere.
Circulating LDL also accumulates in foam cells, but not lipid core, of atherosclerotic
plaques. As noted above, circulating LDL that is not taken up by apo B/E (LDL) receptors
can also enter macrophages through unregulated scavenger receptors. The most
important of these receptors appears to be CD36 (also called scavenger receptor B).
Uptake by these receptors requires chemical modification of LDL particle by enzymatic,
non-oxidative alteration; oxidation, which accelerates accumulation of cholesterol;
glycosylation; or glycoxidation. The oxidation process modifies lysine amino acid on apo
B. Oxidation of LDL can occur in any of cells within artery, including endothelial cells,
macrophages, smooth muscle cells, and T lymphocytes. Vitamin E can reduce uptake of
oxidized LDL by reducing expression of CD36 receptor.
E.
F.
G.
H.
The oxidation of LDL results in formation of isoprostanes which are chemically stable,
free radical catalyzed products of arachidonic acid that are structural isomers of
conventional prostaglandins. They reflect lipid peroxidation and are markers of oxidant
stress in hypercholesterolemia and atherosclerosis. Levels of isoprostanes are increased
in atherosclerotic lesions and localize to foam cells and ECM. Asymptomatic patients
with hypercholesterolemia may have increased urinary excretion of F2 isoprostanes
compared to normal controls.
Elevated plasma concentrations of oxidized LDL are associated with CHD, and patients
with ACS have higher levels of MDA-modified LDL than patients with stable CHD.
MDA-modified LDL is type of oxidatively modified LDL that may be produced when
ischemic injury results in release of aldehydes that substitute lysine residues in apo
B-100.
The prevention of oxidative modification of lipoproteins, as with paraoxonase, is
associated with less severe CAD. In addition, cholesterol-enriched macrophages (called
foam cells) can rupture, releasing oxidized LDL, intracellular enzymes, and oxygen free
radicals that can further damage vessel wall. One potential strategy for preventing
development of atherosclerosis is recombinant adenovirus-mediated gene transfer of
decoy macrophage scavenger receptors that block foam cell formation.
Oxidized LDL particles promote atherosclerosis via one or more of following effects;
however, inflammatory and immune response of endothelial cell to oxidized LDL is
genetically determined and can be seen in inbred mouse strain that is susceptible to
diet-induced atherosclerosis, but not in resistant strain.
Role of oxidized LDL in atherosclerosis
1.
Endothelial damage
2.
Alteration in vascular tone
3.
Monocyte/macrophage recruitment
4.
Increased uptake of LDL by macrophages, with foam cell formation
5.
Induction of growth factors
6.
Increased platelet aggregation
7.
Formation of autoantibodies to oxidized LDL
i.
They act as chemoattractant for monocytes by increasing monocyte binding (via
activation of monocyte β1 integrin), which then develop into tissue macrophages.
In addition, macrophage mobility may be reduced, thereby trapping macrophages
within vessel wall. One study of patients with familial hypercholesterolemia
undergoing selective LDL apheresis reported that hypercholesterolemia was
associated with elevated levels of endothelial LAM-1, VAM-1, and intercellular
adhesion molecule-1 which upregulate endothelial adhesiveness. The levels of
these adhesion molecules were reduced after apheresis.
ii.
LDL particles can promote inflammatory and immune changes via cytokine release
from macrophages and antibody production
iii.
In any circumstance in which LDL-c levels are increased, due, for example, to
abnormality in apo B/E (LDL) receptor, unregulated uptake via scavenger pathway
leads to excess accumulation of modified LDL within macrophages. These foam cells
can rupture, releasing oxidized LDL, intracellular enzymes, and oxygen free radicals
that can further damage vessel wall. Oxidized LDL induces apoptosis of vascular
smooth muscle and human endothelial cells via activation of CPP32-like protease,
which suggests mechanism for response to injury hypothesis of atherosclerosis.
Oxidized LDL can cause disruption of endothelial cell surface and impair endothelial
function, reducing release of NO, which is major mediator of endothelium-
iv.
I.
dependent vasodilation. High levels of cholesterol also increase endothelial
production of oxygen free radicals, which may bind to and inactivate NO.
Treatment with lipid lowering drugs that reduce susceptibility of LDL to oxidation may
reverse some of these changes, resulting in improved vasomotor response to
acetylcholine. Endothelial function can also be improved by administration of NO
precursor L-arginine in hypercholesterolemic rabbits and, in patients with
hypercholesterolemia, vitamin C, folate, and 5-methyltetrahydrofolate, active form of
folic acid; improvement occurs without changes in plasma lipids. Vitamin C and folate
may prevent degradation of NO.
i.
Oxidized LDL causes increase in platelet aggregation and thromboxane release,
which contributes to vasoconstriction and intravascular thrombus formation. LDL
also inhibits NO synthase activity of platelets, which in turn, stimulates platelet
activity and aggregation. L-arginine supplementation attenuates platelet
aggregation in humans, although the magnitude of the effect varies significantly
among individual patients. Oxidized LDL increases activation of redox-sensitive
transcription factors NF-κB and activator protein 1 (AP-1), which in intern increase
expression of a panoply of pro-inflammatory cytokines.
ii.
Oxidized LDL may also play role in plaque instability.
J. Damage to endothelium then promotes platelet adherence and release of cytokines that
stimulate smooth muscle proliferation. Thus, foam cell and platelet accumulation and
K.
smooth muscle proliferation all contribute to formation of atherosclerotic plaque.
Another potential mechanism by which LDL may promote atherosclerosis is by
upregulation of angiotensin II type I receptor. This change may increase functional
response of vascular smooth muscle cells to angiotensin II stimulation. In addition,
angiotensin II type I receptor regulates induction of LOX-1, endothelial receptor for
oxidized LDL that is distinct from macrophage scavenger receptor pathway. The LOX-1
receptor is important in process of oxidized LDL-mediated monocyte adhesion to
coronary artery endothelial cells. Cholesterol lowering with statin drug downregulates
angiotensin II receptor density and reverses elevated BP response to angiotensin II.
4.
Intermediate density lipoprotein (remnant lipoproteins)
A. Although LDL is accepted to be major risk factor in progression of atherosclerosis,
measurement of LDL also includes IDL. Several studies have shown that serum IDL are
predictive of increase incidence of CAD and increased incidence of coronary events in
those with CAD, independently of other factors. This relationship may be particularly
strong in patients with normal total cholesterol levels and those with elevated IDL/HDL
ratio. The MARS study performed analytic ultracentrifugation to determine lipoprotein
subclasses: IDL, but not VLDL or LDL, was associated with progression of carotid artery
intima-media thickness. In another study, normolipidemic men with CAD and subjects
with dysbetalipoproteinemia had elevated levels of IDL when compared to controls;
furthermore, increased levels of IDL were not detected with conventional lipid
5.
screening.
B. Thus, IDL may be major determinant of atherogenic potential of LDL. Similar to LDL, IDL
is taken up by macrophages and can cause foam cell formation and can impair
endothelium-dependent vasomotor function in human coronary arteries.
Very low density lipoprotein (VLDL)
A. The general contribution of hypertriglyceridemia to coronary risk remains uncertain.
Hypertriglyceridemia tends to be associated with low HDL levels; as result, any apparent
increase in CAD may be due to reduction in HDL rather than elevation in TG.
B. Nevertheless, there may be some settings in which TG-containing lipoproteins are
atherogenic. As example, VLDL particles from patients with hypertriglyceridemia are
C.
D.
E.
F.
enriched in apo E. This can lead to conformational change in VLDL particle that facilitates
binding to macrophage scavenger receptor, resulting in unregulated uptake similar to
that seen with oxidized LDL.
LPL hydrolyzes TG contained in core of chylomicrons and VLDL. An Asn291Ser
substitution in LPL causes impaired function of this enzyme and is associated with
increase in plasma TG. Female, but not male, carriers of this mutation have 2-fold
increase in risk of CAD and nonfatal cerebrovascular disease.
A different mechanism occurs in patients with hypertriglyceridemia who overproduce
apo B (as in combined hyperlipidemia). These patients have subspecies of LDL that is
smaller and denser than LDL from patients with normal TG levels. Small, dense LDL
particles bind less avidly to LDL receptor. This prolongs their half-life in circulation,
making these particles more susceptible to oxidative modification and to subsequent
uptake by macrophage scavenger receptors.
Hypertriglyceridemia can also promote atherothrombosis by increasing coagulability and
blood viscosity.
Most patients with elevated levels of VLDL have excess amounts of both TG and
apolipoprotein CIII within these particles. Typically LDL particles contain increased
amounts of these to as well. The role of excess apo C-III in genesis of atherosclerosis is
discussed below.
6.
High density lipoprotein (HDL)
A. HDL, in contrast to LDL and VLDL, has anti-atherogenic properties that include
B.
C.
D.
macrophage cholesterol efflux, anti-oxidation, protection against thrombosis,
maintenance of endothelial function, and maintenance of low blood viscosity through
permissive action on RBC deformability. The net effect is that there is inverse
relationship between plasma HDL-c levels and CV risk. Values > 75 mg/dL are associated
with longevity syndrome.
Macrophage cholesterol efflux is process whereby excess cholesterol in cells and in
atherosclerotic plaques is removed. How this occurs is described above as apo A-I plays
important role. In mouse model, somatic gene transfer of human apo A-I can prevent
development of atherosclerosis or reverse preexisting atherosclerosis. A similar benefit
in animals can be seen with oral administration of apo A-I mimetic peptides,
independent of changes in serum total or HDL-c. On the other hand, mutations in apo A-I
can lead to lower plasma levels of apo A-I and HDL-c and can increase risk of
atherosclerosis.
The anti-oxidant properties of HDL particles may be important in humans. In group of
men with CAD who were atypical in that they had high HDL-c levels (≥ 84 mg/dL), HDL
particles were ineffective in mitigating oxidative stress and reducing ex vivo
inflammatory responses compared to control group with similar lipid profile but without
CHD.
The anti-oxidant properties of HDL may be due in part to activity of HDL-associated
enzymes such as paraoxonase. Paraoxonase inhibits oxidation of LDL in vitro and genetic
deletion of paraoxonase is associated with increased susceptibility of LDL to oxidation in
vivo. Two pieces of evidence support the antioxidant role of HDL-associated
paraoxonase in humans.
i.
Small HDL particles exhibit more antioxidant activity than large particles, due to
stronger attachment of paraoxonase to these particles.
ii.
Higher paraoxonase activity measures were associated with both a lower
prevalence of cardiovascular disease and a lower rate of future major adverse
cardiac events in a prospective evaluation of 1399 patients.
E. HDL and apo A-I also inhibit generation of calcium-induced procoagulant activity on
F.
G.
erythrocytes via stabilization of cell membrane. This membrane stabilizing action
prevents transbilayer diffusion of anionic lipids that is required for prothrombin
activation, thereby minimizing thrombus formation.
HDL improves endothelial function by increasing eNOS production and inhibiting cellular
adhesion molecule expression.
HDL plays an important role in glucose homeostasis through its effect on increased
pancreatic beta cell production of insulin.
7.
Triglyceride rich lipoproteins and apo C-III
A. Elevations in serum TG are associated with an increased risk for atherosclerosis and
some experts consider them to be an independent risk factor. In addition, elevated
levels of apo C-III are correlated with and may be causative for hypertriglyceridemia.
B. Excessive apo C-III on the surface of TG rich lipoproteins (VLDL or LDL) may contribute to
the development of atherosclerosis by at least three mechanisms.
i.
Delaying lipolysis of VLDL and inhibiting its uptake and clearance from the plasma.
ii.
Augmenting arterial inflammation through effects on both peripheral monocytes
and endothelial cells.
iii.
Interfering with normal nitric oxide function in endothelial cells, perhaps through
interfering with insulin signaling, and thus causing endothelial dysfunction.
8.
Lipoprotein (a)
A. Lp (a), the specialized form of LDL, is a risk factor for the development of atherosclerotic
events and evidence strongly suggests that it is causative. This issue is discussed
separately.
SUMMARY
1. Lipids, such as cholesterol and triglycerides, are insoluble in plasma and circulating lipid is
carried in lipoproteins that transport the lipid to various tissues for energy utilization, lipid
deposition, steroid hormone production, and bile acid formation. The lipoprotein consists of
esterified and unesterified cholesterol, triglycerides, and phospholipids, and protein. The
protein components of the lipoprotein are known as apolipoproteins (apo) or apoproteins.
2.
3.
4.
5.
6.
The different apolipoproteins serve as cofactors for enzymes and ligands for receptors.
Abnormal lipoprotein metabolism is a major predisposing factor to atherosclerosis. It is
estimated that a dyslipidemia is present in over 70% of patients with premature coronary
heart disease.
Elevated plasma concentrations of apo B-100 containing lipoproteins (low density and very
low density lipoprotein) can induce the development of atherosclerosis even in the absence
of other risk factors. It has been proposed that the initiating event in atherogenesis is the
subendothelial retention of apo B-100 containing lipoproteins.
The general contribution of hypertriglyceridemia to coronary risk remains uncertain.
Hypertriglyceridemia tends to be associated with low HDL levels; as a result, any apparent
increase in CHD may be due to the reduction in HDL rather than the elevation in triglycerides.
HDL, in contrast to LDL and VLDL, has anti-atherogenic properties that include macrophage
cholesterol efflux, anti-oxidation, protection against thrombosis, maintenance of endothelial
function, and maintenance of low blood viscosity through a permissive action on red cell
deformability.
Lp(a), the specialized form of LDL, is a risk factor for the development of atherosclerotic
events and evidence strongly suggests that it is causative. This issue is discussed separately.