438 Chapter 13
Lipids, including cholesterol, are carried in the blood attached
to protein carriers ( fig. 13.32 ; also see chapter 18, table 18.8).
Cholesterol is carried to the arteries by plasma proteins called
low-density lipoproteins (LDLs). LDLs are derived from very
low-density lipoproteins (VLDLs), which are small, protein-coated
droplets produced by the liver and composed of cholesterol, tri-
glycerides, free fatty acids, and phospolipids. After enzymes
in various organs remove most of the triglycerides, the VLDLs
become LDLs that transport cholesterol to the organs.
Cells in different organs contain receptors for the proteins
(called apolipoproteins ) in LDLs. When these apolipoproteins
bind to their receptors, the cell engulfs the LDL particles by
receptor-mediated endocytosis (chapter 3; see fig. 3.4). Most
LDL particles are removed in this way by the liver. However, the
uptake and accumulation of a particular LDL protein, apolipo-
protein B, into the subendothelial connective tissue of an artery
is believed to initiate the formation of an atherosclerotic plaque.
Apolipoprotein B, enhanced by oxidation (discussed shortly),
acts on the endothelium to promote the entry of monocytes
into the lesion and the conversion of the monocytes into mac-
rophages. Macrophages ingest these lipoproteins and become
foam cells, which promote the progression of the disease.
People who eat a diet high in cholesterol and saturated
fat, and people with familial hypercholesteremia, have a high
blood LDL concentration because their livers have a low num-
ber of LDL receptors. With fewer LDL receptors, the liver is
less able to remove the LDL from the blood and more LDL is
available to enter the endothelial cells of arteries.
High-density lipoprotein (HDL), in contrast, offers pro-
tection against atherosclerosis by carrying cholesterol away
from the arterial wall. In the development of atherosclerosis,
monocytes migrate through the arterial endothelium to the
intima, where they become macrophages that are able to engulf
oxidized LDLs (discussed shortly). The cholesterol-engorged
macrophages are known as foam cells and play an important
role in the development of the atherosclerotic lesion. This
progress is retarded by HDL, which accepts cholesterol from
the foam cells and carries it through the blood to the liver for
metabolism. HDL levels are largely determined by genetics, but
it is known that HDL levels are higher, and the risk of athero-
sclerosis is lower, in women (prior to menopause) than in men,
and in people who exercise regularly. HDL levels are higher in
marathon runners than in joggers, and are higher in joggers than
in sedentary people. Drugs that help raise HDL levels include
the statins (such as Lipitor), the fibrates, and high doses of the
vitamin niacin.Figure 13.32 Structure of a lipoprotein. There is
a core of nonpolar triglycerides and cholesterol esters coated
by proteins (apolipoproteins), phospholipids, and some free
cholesterol.
Cholesterol esters
Triglycerides
Polypeptides
(apolipoproteins)Free
cholesterolPhospholipidCLINICAL APPLICATION
Statins are drugs that help lower LDL-cholesterol concentra-
tions to reduce the risk of atherosclerosis. Statins are inhibitors
of HMG-coenzyme A reductase, the enzyme that catalyzes
the rate-limiting step in cholesterol synthesis. As a result,
the statins reduce the ability of liver cells to produce choles-
terol. The lowered intracellular cholesterol then stimulates the
production of more LDL receptors in the plasma membrane,
allowing the liver cells to engulf more LDL-cholesterol from
the blood. This lowers the blood LDL-cholesterol concentra-
tion so that less will enter the endothelial cells of the arteries.
Statins also have other beneficial effects: they slightly increase
the HDL level, and they reduce inflammation, which promotes
atherosclerosis as described next.Inflammation and Atherosclerosis
Notice the important roles played by cells of the immune
system—particularly monocytes and lymphocytes—in the
development and progression of atherosclerosis. Atheroscle-
rosis is now believed to be an inflammatory disease to a sig-
nificant degree. This is emphasized by the recent evidence that
measurement of blood C-reactive protein, a marker of inflam-
mation, is actually a stronger predictor of atherosclerotic heart
disease than the blood LDL cholesterol level.
The inflammatory process may be instigated by oxida-
tive damage to the artery wall. When endothelial cells engulf
LDL, they oxidize it to a product called oxidized LDL. Evi-
dence suggests that oxidized LDL contributes to endothelial
cell injury, migration of monocytes and lymphocytes into the
tunica interna, conversion of monocytes into macrophages, and
other events that occur in the progression of atherosclerosis.
Because oxidized LDL seems to be so important in the
progression of atherosclerosis, it would appear that antioxi-
dant compounds could be used to treat this condition or help
to prevent it. The antioxidant drug probucol, as well as vita-
min C, vitamin E, and beta-carotene, which are antioxidants
(chapter 19, section 19.1), have decreased the formation of
oxidized LDL in vitro but have had only limited success so far
in treating atherosclerosis.