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

More than 900 mutations of the LDL receptor gene have
been identified in association with defective or absent
LDL receptors that cause high levels of plasma LDL and
familial hypercholesterolemia.
ApoB-100, the primary apoprotein of LDL, is the ligand that
binds LDL to its receptor. Residues 3000-3700 in the carboxylterminal
sequence are critical for binding. Mutations in this region
disrupt binding and also are a cause of autosomal dominant hypercholesterolemia
(familial defective apoB-100). A third disorder
causing autosomal dominant hypercholesterolemia is caused by
gain of function mutations in the gene encoding PCSK9, a serine
protease that destroys LDL receptors in the liver (Horton et al., 2007).
Autosomal recessive hypercholesterolemia closely resembles
familial hypercholesterolemia but is not caused by LDL receptor
mutations.
The liver expresses a large complement of LDL
receptors and removes ~75% of all LDL from the
plasma. Consequently, manipulation of hepatic LDL
receptor gene expression is a most effective way to modulate
plasma LDL-C levels. Thyroxine and estrogen
enhance LDL receptor gene expression, which explains
their LDL-C–lowering effects.
The most effective dietary alteration (decreased
consumption of saturated fat and cholesterol) and pharmacological
treatment (statins) for hypercholesterolemia
act by enhancing hepatic LDL receptor
expression. Regulation of LDL receptor expression is
part of a complex process by which cells regulate their
free cholesterol content. This regulatory process is
mediated by transcription factors called sterol regulatory
element binding proteins (SREBPs) and SREBP
cleavage activating protein (Scap) (Radhakrishnan et
al., 2008). Scap is both a sensor of cholesterol content
in the endoplasmic reticulum (ER) and an escort of
SREBPs from the ER to the Golgi apparatus. In the
Golgi apparatus, SREBPs undergo proteolytic cleavage,
and a dimer of the amino-terminal domain, transported
by importin β, translocates to the nucleus, where
it activates expression of the LDL receptor gene and of
other genes encoding enzymes involved in cholesterol
biosynthesis. Increased ER cholesterol content binds
Scap, precluding Scap from escorting SREBP to the
Golgi apparatus for processing and ultimately from
reaching the nucleus.
LDL becomes atherogenic when modified by oxidation
(Witztum and Steinberg, 2001), a required step for LDL uptake by
the scavenger receptors of macrophages. This process leads to foamcell
formation in arterial lesions. At least two scavenger receptors
(SRs) are involved (SR-AI/II and CD36). Knocking out either receptor
in transgenic mice retards the uptake of oxidized LDL by
macrophages. Expression of the two receptors is regulated differently:
SR-AI/II appears to be expressed more in early atherogenesis, and
CD36 expression is greater as foam cells form during lesion progression.
Despite the large body of evidence implicating oxidation
of LDL as a requisite step during atherogenesis, controlled clinical
trials have not unequivocally demonstrated the efficacy of antioxidant
vitamins in preventing vascular disease.
High-Density Lipoproteins. The metabolism of HDL is
complex because of the multiple mechanisms by which
HDL particles are modified in the plasma compartment.
ApoA-I is the major HDL apoprotein, and its plasma
concentration is a more powerful inverse predictor of
CHD risk than is the HDL-C level (Mahley et al., 2008).
ApoA-I synthesis is required for normal production of
HDL. Mutations in the apoA-I gene that cause HDL
deficiency are variable in their clinical expression and
often are associated with accelerated atherogenesis.
Conversely, overexpression of apoA-I in transgenic mice
protects against experimentally induced atherogenesis.
Mature HDL can be separated by ultracentrifugation into
HDL 2
(d = 1.063-1.125 g/mL), which are larger, more cholesterolrich
lipoproteins (70-100 Å in diameter), and HDL 3
(d = 1.125-1.21
g/mL), which are smaller particles (50-70 Å in diameter). In addition,
two major subclasses of mature HDL particles in the plasma
can be differentiated by their content of the major HDL apoproteins,
apoA-I and apoA-II (Movva and Rader, 2008). Epidemiologic evidence
in humans suggests that apoA-II may be atheroprotective
(Birjmohun et al., 2007; Movva and Rader, 2008).
Lipoprotein particles may be distinguished by their electrophoretic
mobities: mature HDL particles have α mobility; LDL
particles show β mobility. The precursor of most of the α-migrating
plasma HDL is a discoidal particle containing apoA-I and phospholipid,
called pre-β1 HDL because of its pre-β1 electrophoretic mobility.
Pre-β1 HDL are synthesized by the liver and the intestine, and
they also arise when surface phospholipids and apoA-I of chylomicrons
and VLDL are lost as the triglycerides of these lipoproteins
are hydrolyzed. Discoidal pre-β1 HDL can then acquire free unesterified
cholesterol from the cell membranes of tissues, such as arterial
wall macrophages. Two macrophage membrane transporters,
ABCA1 and ABCG1, promote the efflux of cholesterol from
macrophages of humans studied in vivo. Prior studies in vitro suggested
that another transport protein, class B, type I scavenger receptor
(SR-BI) facilitates cholesterol egress from macrophages to HDL,
but in vivo studies in humans do not support an important role for
SR-BI in this process (Wang et al., 2007). However, SR-BI in the
liver facilitates the uptake of cholesteryl esters from HDL without
internalizing and degrading the lipoproteins.
The membrane transporter ABCA1 facilitates the
transfer of free cholesterol from cells to HDL (Attie,
2007). When ABCA1 is defective, the acquisition of
cholesterol by HDL is greatly diminished, and HDL levels
are markedly reduced because poorly lipidated nascent
HDL are metabolized rapidly. Loss-of-function
mutations of ABCA1 cause the defect observed in
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CHAPTER 31
DRUG THERAPY FOR HYPERCHOLESTEROLEMIA AND DYSLIPIDEMIA