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826 PA R T V / Health Promotion and Disease Prevention
jor lipoprotein, apo A-I to form incomplete (or nascent) lipid-
poor HDL precursors. These precursors acquire excess cholesterol
VLDL through a variety of mechanisms outlined below. One early step is
the cholesterol efflux from macrophages mediated by the mem-
brane protein, adenosine triphosphate binding cassette trans-
porter A-1 (ABCA1), one of a family of proteins that transport
32
molecules across cell membranes. It is proposed that ABCA1 al-
LDL VLDL lows binding with apo A-I in nascent HDL to form more mature
p
Receptors Remnant HDL particles. 33 Other steps include the action of the enzyme,
lecithin cholesterol acyltransferase, which converts free cholesterol
in the tissues into an HDL cholesteryl ester core. 34,35 Apo A-I has
been shown to activate lecithin cholesterol acyltransferase and
may influence the activity of the CETP. CETP facilitates the ex-
change of cholesterol esters for the triglycerides in apo B lipopro-
LDL
Other Sites teins including LDL and VLDL. Apo C-II is a cofactor for LPL.
36
In the presence of circulating triglycerides, apo C-II moves from
■ Figure 36-2 The endogenous lipid transport system originates in HDL to the triglyceride particle, activating LPL and promoting
37
the liver. LDLs provide essential cholesterol to the tissue cells. the catabolism of VLDL. This mechanism, in part, explains the
clinical observation of an inverse association between high triglyc-
erides and low HDL levels. A third apoprotein, apo E, is thought
to facilitate direct transfer of cholesterol esters to hepatocyte re-
ceptors. 37 Cholesterol esters are then excreted in bile or bile
inhibited LDL receptor activity. High LDL levels also can result acids. 38
from a decrease in clearance of LDL because of a deficiency in Although the protective effect of HDL has been linked to its
LDL receptors. This deficiency may be caused by genetic abnor- role in the reverse transport of cholesterol, it is clear that other fac-
malities in the structure of the receptor binding sites (where tors, particularly genetic factors, determine coenzyme, apopro-
apolipoproteins bind) or by a decrease in LDL receptors on the tein, and receptor activity. In fact, it is estimated that 50% to 70%
surface of cells. In addition, genetic mutation in apoproteins, of the variation in HDL is genetically determined influencing the
particularly apo E and apo B-100, can result in decreased cho- receptor and enzyme activity involved in the catabolism of
lesterol clearance. The metabolic consequence is an increased HDL. Deletions or mutations of the apo A-I gene results in very
39
blood level of this atherogenic lipoprotein and the synthesis of reduced HDL levels (e.g., A-I Milano) and may be associated with
cholesterol within cells, a process normally suppressed by LDL increased atherosclerosis. One important recent discovery was
uptake. that of the ABCA1 genetic defect manifested in Tangiers disease
as a disorder with extremely low HDL levels and with accelerated
cholesterol tissue deposition. 32,40
Recent studies have found that plasma HDL levels are regu-
REVERSE CHOLESTEROL lated by a class of enzymes including LPL, HL, and endothelial
TRANSPORT lipase (EL). 41 LPL is synthesized by adipose and skeletal muscle
cells and acts primarily on the hydrolysis of triglycerides. HL is
Studies have consistently observed a protective effect of high-den- synthesized in the liver cells and acts on triglyceride and phos-
sity lipoprotein (HDL). For example, high levels of HDL have pholipid catabolism. EL is synthesized in endothelial cells and
been associated with a reduced risk of CVD. 8,27 It has been sug- appears to regulate HDL levels by preventing the transfer of
gested that the protective effect of HDL is greater than the athero- triglycerides and remnant particles to HDL. Evidence includes
genic effect of LDL cholesterol. For men in the Framingham genetically modified animal models that over express EL show a
Heart Study, a 50% reduction in coronary risk was found with marked decrease in HDL levels 42 and human studies observing
28
every 10-mg/dL increment in HDL. Studies have indicated that genetic variants in the EL gene in persons with high HDL
increased apo A-I levels may also be inversely related to CVD. 29 levels. 39
Clinical trial data demonstrated that pharmacological increases of While we have gained a greater understanding of the role of
HDL cholesterol significantly decreased coronary and stroke HDL in reverse cholesterol transport, studies also suggest that
events among patients with CVD. 30 HDL may have both pro- and anti-inflammatory properties and
At present, the synthesis and metabolism of HDL is not fully in the face of inflammatory states, HDL may be altered to become
elucidated. Over the last decade, research directed at identifying proinflammatory. 43,44 This may explain the finding that athero-
therapeutics to raise HDL levels has led to an increased under- sclerosis (as an inflammatory disease) is observed even in persons
standing of the complex mechanisms involved in HDL synthesis with normal to high HDL levels. Studies have also suggested that
and its role in reverse cholesterol transport (the transport of cho- HDL may act as an antioxidant, by preventing the oxidation of
lesterol from the tissues to the liver resulting in biliary excretion LDL, thus rendering it less atherogenic, 45,46 or by attenuating the
of cholesterol). 31 expression of other enzymes and molecules that alter endothelial
HDL particles are composed of proteins 50%, phospho- dilation and chemotactic properties. 47
lipids 30% and cholesterol 25%, triglycerides 5%, and as- At present, there are two major subclasses of HDL based on
sorted lipoprotein-processing enzymes. 31 The intestine and liver density and apoprotein composition. HDL 3 is richer in apo A-II
are responsible for synthesizing the precursors of HDL and its ma- than HDL 2 , which has a higher concentration of apo A-I. 29