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

Another ACAT enzyme, ACAT-1, is expressed in
macrophages, including foam cells, adrenocortical cells, and skin
sebaceous glands. Although ACAT-1 esterifies cholesterol and promotes
foam-cell development, ACAT-1 knockout mice do not have
reduced susceptibility to atherosclerosis.
chylomicron metabolism include orlistat, which inhibits hydrolysis
of dietary triglycerides, insulin replacement in patients with type I
diabetes mellitus (insulin has a “permissive effect” on LPL-mediated
triglyceride hydrolysis), and fibrates, which enhance LPL gene
expression.
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After gaining entry to the circulation via the thoracic
duct, chylomicrons are metabolized initially at the
capillary luminal surface of tissues that synthesize
lipoprotein lipase (LPL), a triglyceride hydrolase
(Figure 31–1). These tissues include adipose tissue,
skeletal and cardiac muscle, and breast tissue of lactating
women. As the triglycerides are hydrolyzed by
LPL, the resulting free fatty acids are taken up and
utilized by the adjacent tissues. The interaction of chylomicrons
and LPL requires apoC-II as an absolute
cofactor. The absence of functional LPL or functional
apoC-II prevents the hydrolysis of triglycerides in chylomicrons
and results in severe hypertriglyceridemia
and pancreatitis during childhood or even infancy (chylomicronemia
syndrome). Potentially atherogenic roles
for LPL have been identified that affect the metabolism
and uptake of atherogenic lipoproteins by the liver and
the arterial wall and that impact the dyslipidemia of
insulin resistance (Brown and Rader, 2007).
The plasma concentration of chylomicrons is primarily
controlled by reducing dietary fat consumption. Drugs that affect
INTESTINE
Bile acids
LDL
LIVER receptors
Remnant
receptors
Dietary fat + cholesterol
Chylomicrons
Adipose
tissue
FFA
Chylomicron Remnants. After LPL-mediated removal of
much of the dietary triglycerides, the chylomicron remnants,
which still contain all of the dietary cholesterol,
detach from the capillary surface and within minutes
are removed from the circulation by the liver (Figure
31–1). First, the remnants are sequestered by the interaction
of apoE with heparan sulfate proteoglycans on
the surface of hepatocytes and are processed by hepatic
lipase (HL), further reducing the remnant triglyceride
content. Next, apoE mediates remnant uptake by interacting
with the hepatic LDL receptor or the LDL receptor–related
protein (LRP) (Lillis et al., 2008). The
multifunctional LRP recognizes a variety of ligands,
including apoE, and several ligands unrelated to lipid
metabolism.
In plasma lipid metabolism, the LRP is important because it
is the backup receptor responsible for the uptake of apoE-enriched
remnants of chylomicrons and VLDL. Cell-surface heparan sulfate
proteoglycans facilitate the interaction of apoE-containing remnant
lipoproteins with the LRP, which mediates uptake by hepatocytes.
Inherited absence of either functional HL (very rare) or functional
apoE impedes remnant clearance by the LDL receptor and the LRP,
FFA
VLDL
LPL
ApoE mediated
ApoB mediated
ApoE mediated
LPL
FFA
IDL
Chylomicron
remnants
Peripheral
tissues
(with LDL
receptors)
LPL
HL
LDL
LPL
HL
CHAPTER 31
DRUG THERAPY FOR HYPERCHOLESTEROLEMIA AND DYSLIPIDEMIA
Figure 31–1. The major pathways involved in the metabolism of chylomicrons synthesized by the intestine and VLDL synthesized by
the liver. Chylomicrons are converted to chylomicron remnants by the hydrolysis of their triglycerides by LPL. Chylomicron remnants
are rapidly cleared from the plasma by the liver. “Remnant receptors” include the LDL receptor–related protein (LRP), LDL receptors,
and perhaps other receptors. Free fatty acid (FFA) released by LPL is used by muscle tissue as an energy source or taken up and
stored by adipose tissue. HL, hepatic lipase; IDL, intermediate-density lipoproteins; LDL, low-density lipoproteins; LPL, lipoprotein
lipase; VLDL, very-low-density lipoproteins.