Page 641 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 35 Agents Used in Dyslipidemia 627

retrieval, cytotoxic effects on the endothelium, increased oxidation Synthesis & Catabolism
of lipoproteins, and stimulation of thrombogenesis. Diabetes, also
a major risk factor, is another source of oxidative stress. A. Chylomicrons
Normal coronary arteries can dilate in response to ischemia, Chylomicrons are formed in the intestine and carry triglycerides
increasing delivery of oxygen to the myocardium. This process of dietary origin, unesterified cholesterol, and cholesteryl esters.
is mediated by nitric oxide, acting on smooth muscle cells of They transit the thoracic duct to the bloodstream.
the arterial media. The release of nitric oxide from the vascular Triglycerides are removed from the chylomicrons in extrahe-
endothelium is impaired by atherogenic lipoproteins, thus aggra- patic tissues through a pathway shared with VLDL that involves
vating ischemia. Reducing levels of atherogenic lipoproteins and hydrolysis by the lipoprotein lipase (LPL) system. Decrease
inhibiting their oxidation restores endothelial function. in particle diameter occurs as triglycerides are depleted. Surface
Because atherogenesis is multifactorial, therapy should be lipids and small apoproteins are transferred to HDL. The resultant
directed toward all modifiable risk factors. Atherogenesis is a chylomicron remnants are taken up by receptor-mediated endocy-
dynamic process. Quantitative angiographic trials have demon- tosis into hepatocytes.
strated net regression of plaques during aggressive lipid-lowering
therapy. Primary and secondary prevention trials have shown B. Very-Low-Density Lipoproteins
significant reduction in mortality from new coronary events and VLDL are secreted by liver and export triglycerides to peripheral
in all-cause mortality. tissues (Figure 35–1). VLDL triglycerides are hydrolyzed by
LPL, yielding free fatty acids for storage in adipose tissue and for
oxidation in tissues such as cardiac and skeletal muscle. Deple-
■ PATHOPHYSIOLOGY OF tion of triglycerides produces remnants (IDL), some of which
HYPERLIPOPROTEINEMIA undergo endocytosis directly into hepatocytes. The remainder are
converted to LDL by further removal of triglycerides mediated by
hepatic lipase. This process explains the “beta shift” phenomenon,
NORMAL LIPOPROTEIN the increase of LDL (beta-lipoprotein) in serum as hypertriglyc-
METABOLISM eridemia subsides. Increased levels of LDL can also result from
increased secretion of VLDL and from decreased LDL catabolism.
Structure
C. Low-Density Lipoproteins
Lipoproteins have hydrophobic core regions containing cholesteryl LDL are catabolized chiefly in hepatocytes and other cells after
esters and triglycerides surrounded by unesterified cholesterol, receptor-mediated endocytosis. Cholesteryl esters from LDL
phospholipids, and apoproteins. Certain lipoproteins contain are hydrolyzed, yielding free cholesterol for the synthesis of cell
very high-molecular-weight B proteins that exist in two forms: membranes. Cells also obtain cholesterol by synthesis via a path-
B-48, formed in the intestine and found in chylomicrons and way involving the formation of mevalonic acid by HMG-CoA
their remnants; and B-100, synthesized in liver and found in reductase. Production of this enzyme and of LDL receptors is
VLDL, VLDL remnants (IDL), LDL (formed from VLDL), and transcriptionally regulated by the content of cholesterol in the
Lp(a) lipoproteins. HDL consist of at least 20 discrete molecular cell. Normally, about 70% of LDL is removed from plasma by
species containing apolipoprotein A-I (apo A-I). About 100 other hepatocytes. Even more cholesterol is delivered to the liver via IDL
proteins are known to be distributed variously among the HDL and chylomicrons. Unlike other cells, hepatocytes can eliminate
species.
cholesterol by secretion in bile and by conversion to bile acids.

A CR ON Y MS D. Lp(a) Lipoprotein
Apo Apolipoprotein Lp(a) lipoprotein is formed from LDL and the (a) protein, linked
by a disulfide bridge. The (a) protein is highly homologous with
CETP Cholesteryl ester transfer protein
plasminogen but is not activated by tissue plasminogen activator.
CK Creatine kinase
It occurs in a number of isoforms of different molecular weights.
HDL High-density lipoproteins Levels of Lp(a) vary from nil to over 2000 nM/L and are deter-
HMG-CoA 3-Hydroxy-3-methylglutaryl-coenzyme A mined chiefly by genetic factors. Lp(a) is found in atherosclerotic
IDL Intermediate-density lipoproteins plaques and contributes to coronary disease by inhibiting throm-
LCAT Lecithin:cholesterol acyltransferase bolysis. It is also associated with aortic stenosis. Levels are elevated
in certain inflammatory states. The risk of coronary disease is
LDL Low-density lipoproteins
strongly related to the level of Lp(a). A common variant (I4399M)
Lp(a) Lipoprotein(a)
in the coding region is associated with elevated levels.
LPL Lipoprotein lipase
PCSK9 Proprotein convertase subtilisin/kexin type 9 E. High-Density Lipoproteins
PPAR Peroxisome proliferator-activated receptor The apoproteins of HDL are secreted largely by the liver and
VLDL Very-low-density lipoproteins intestine. Much of the lipid comes from the surface monolayers of