DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

878 to as “small, dense LDL”) (Grundy et al., 2004a). The
metabolic syndrome affects ~25% of adults and is common
in CVD patients; hence, identification of moderate
hypertriglyceridemia in a patient, even if the total cholesterol
level is normal, should trigger an evaluation to identify
insulin-resistant patients with this disorder.
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
PLASMA LIPOPROTEIN METABOLISM
Lipoproteins are macromolecular assemblies that contain
lipids and proteins. The lipid constituents include
free and esterified cholesterol, triglycerides, and phospholipids.
The protein components, known as
apolipoproteins or apoproteins, provide structural stability
to the lipoproteins and also may function as ligands
in lipoprotein–receptor interactions or as cofactors
in enzymatic processes that regulate lipoprotein metabolism.
In all spherical lipoproteins, the most waterinsoluble
lipids (cholesteryl esters and triglycerides) are
core components, and the more polar, water-soluble
components (apoproteins, phospholipids, and unesterified
cholesterol) are located on the surface. The major
classes of lipoproteins and a number of their properties
are summarized in Table 31–1.
Table 31–2 describes apoproteins that have welldefined
roles in plasma lipoprotein metabolism. These
apolipoproteins include apolipoprotein (apo) A-I,
apoA-II, apoA-IV, apoA-V, apoB-100, apoB-48, apoC-
I, apoC-II, apoC-III, apoE, and apo(a). Except for
apo(a), the lipid-binding regions of all apoproteins contain
amphipathic helices that interact with the polar,
hydrophilic lipids (such as surface phospholipids) and
with the aqueous plasma environment in which the
lipoproteins circulate. Differences in the non–lipid-binding
regions determine the functional specificities of the
apolipoproteins.
Chylomicrons. Chylomicrons are synthesized from the
fatty acids of dietary triglycerides and cholesterol
absorbed from the small intestine by epithelial cells.
Fat-soluble vitamins also are incorporated into chylomicrons
after absorption.
Chylomicrons, the largest plasma lipoproteins, are the only
lipoproteins that float to the top of a tube of plasma that has been
allowed to stand undisturbed for 12 hours. The buoyancy of chylomicrons
reflects their high fat content (98-99%), of which 85% is
from fatty acids of dietary triglycerides. In chylomicrons, the ratio
of triglycerides to cholesterol is ~10 or greater. In normolipidemic
individuals, chylomicrons are present in plasma for 3-6 hours after
a fat-containing meal has been ingested. After a fast of 10-12 hours,
no chylomicrons remain.
Intestinal cholesterol and plant sterol absorption
is mediated by Niemann-Pick C1–Like 1 protein
(NPC1L1), which appears to be the target of ezetimibe,
a cholesterol absorption inhibitor (Davis and Altmann,
2009). Plant sterols, unlike cholesterol, are not normally
esterified and incorporated into chylomicrons.
Two ATP-binding cassette (ABC) half-transporters,
ABCG5 and ABCG8, which reside on the apical
plasma membrane of enterocytes, channel plant sterols
back into the intestinal lumen, preventing their assimilation
into the body. Patients with the autosomal recessive
disorder sitosterolemia have mutations in either of
the genes that encode ABCG5 and ABCG8. As a result,
they absorb unusually large amounts of plant sterols,
fail to excrete dietary sterols into the bile, and thus
accumulate plant sterols in the blood and tissues; this
accumulation is associated with tendon and subcutaneous
xanthomas and a markedly increased risk of premature
CHD.
Triglyceride synthesis is regulated by diacylglycerol
transferase in many tissues. After their synthesis in
the endoplasmic reticulum, triglycerides are transferred
by microsomal triglyceride transfer protein (MTP) to
the site where newly synthesized apoB-48 is available
to form chylomicrons.
The apolipoproteins of chylomicrons include some that are
synthesized by intestinal epithelial cells (apoB-48, apoA-I, and
apoA-IV), and others acquired from HDL (apoE and apoC-I, C-II,
and C-III) after chylomicrons have been secreted into the lymph and
enter the plasma (Table 31–2). The apoB-48 of chylomicrons is one
of two forms of apoB present in lipoproteins. ApoB-48, synthesized
only by intestinal epithelial cells, is unique to chylomicrons. ApoB-
100 is synthesized by the liver and incorporated into VLDL and
intermediate-density lipoproteins (IDL) and LDL, which are products
of VLDL catabolism. The apparent molecular weight of apoB-
48 is 48% that of apoB-100, which accounts for the name
“apoB-48.” The amino acid sequence of apoB-48 is identical to the
first 2152 of the 4536 residues of apoB-100. An RNA-editing mechanism
unique to the intestine accounts for the premature termination
of the translation of the apoB-100 mRNA. ApoB-48 lacks the portion
of the sequence of apoB-100 that allows apoB-100 to bind to the
LDL receptor, so apoB-48 functions primarily as a structural component
of chylomicrons.
Dietary cholesterol is esterified by the type 2
isozyme of acyl coenzyme A:cholesterol acyltransferase
(ACAT-2). ACAT-2 is found in the intestine and
in the liver, where cellular free cholesterol is esterified
before triglyceride-rich lipoproteins [chylomicrons and
very-low-density lipoproteins (VLDL)] are assembled.
In the intestine, ACAT-2 regulates the absorption of
dietary cholesterol and thus may be a potential pharmacological
target for reducing blood cholesterol levels.