Normal coronary arteries can dilate in response to ischemia, increasing delivery of oxygen to the myocardium. This process is mediated by nitric oxide, acting on smooth muscle cells of the arterial media. The release of nitric oxide from the vascular endothelium is impaired by atherogenic lipoproteins, thus aggravating ischemia. Reducing levels of atherogenic lipoproteins and inhibiting their oxidation restores endothelial function.
Because atherogenesis is multifactorial, therapy should be directed toward all modifiable risk factors. Atherogenesis is a dynamic process. Quantitative angiographic trials have demonstrated net regression of plaques during aggressive lipid-lowering therapy. Primary and secondary prevention trials have shown significant reduction in mortality from new coronary events and in all-cause mortality.
Lipoproteins have hydrophobic core regions containing cholesteryl esters and triglycerides surrounded by unesterified cholesterol, phospholipids, and apoproteins. Certain lipoproteins contain very high-molecular-weight B proteins that exist in two forms: B-48, formed in the intestine and found in chylomicrons and their remnants; and B-100, synthesized in liver and found in VLDL, VLDL remnants (IDL), LDL (formed from VLDL), and Lp(a) lipoproteins. HDL consist of at least 20 discrete molecular species containing apolipoprotein A-I (apo A-I). About 100 other proteins are known to be distributed variously among the HDL species.
A. Chylomicrons
Chylomicrons are formed in the intestine and carry triglycerides of dietary origin, unesterified cholesterol, and cholesteryl esters. They transit the thoracic duct to the bloodstream.
Triglycerides are removed from the chylomicrons in extrahepatic tissues through a pathway shared with VLDL that involves hydrolysis by the lipoprotein lipase (LPL) system. Decrease in particle diameter occurs as triglycerides are depleted. Surface lipids and small apoproteins are transferred to HDL. The resultant chylomicron remnants are taken up by receptor-mediated endocytosis into hepatocytes.
B. Very-Low-Density Lipoproteins
VLDL are secreted by liver and export triglycerides to peripheral 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. Depletion of triglycerides produces remnants (IDL), some of which 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, the increase of LDL (beta-lipoprotein) in serum as hypertriglyceridemia subsides. Increased levels of LDL can also result from increased secretion of VLDL and from decreased LDL catabolism.
C. Low-Density Lipoproteins
LDL are catabolized chiefly in hepatocytes and other cells after receptor-mediated endocytosis. Cholesteryl esters from LDL are hydrolyzed, yielding free cholesterol for the synthesis of cell membranes. Cells also obtain cholesterol by synthesis via a pathway involving the formation of mevalonic acid by HMG-CoA reductase. Production of this enzyme and of LDL receptors is transcriptionally regulated by the content of cholesterol in the cell. Normally, about 70% of LDL is removed from plasma by hepatocytes. Even more cholesterol is delivered to the liver via IDL and chylomicrons. Unlike other cells, hepatocytes can eliminate cholesterol by secretion in bile and by conversion to bile acids.
D. Lp(a) Lipoprotein