Abstract

Epidemiological studies have shown that hypertriglyceridemia and low HDL-cholesterol were both associated with an increased risk of coronary heart disease. Furthermore, hypertriglyceridemia is now recognized as an independent risk factor for coronary artery disease. Secondary prevention trials (e.g., LOCAT, BECAIT, BIP and DAIS) in coronary artery disease with drugs acting primarily on triglycerides (e.g., the PPAR-alpha activators bezafibrate, fenofibrate and gemfibrozil) have shown that reducing triglycerides and increasing HDL-cholesterol, without significantly affecting LDL-cholesterol, slows down coronary artery luminal narrowing. Furthermore, the VA-HIT study recently showed that gemfibrozil decreased coronary artery disease mortality in secondary prevention trials, partly by increasing HDL-cholesterol. The peroxisome proliferator-activated receptors (PPARs) (i.e., PPAR-alpha, -beta(delta) and -gamma) form a subfamily of the nuclear receptor gene family. Whereas all PPARs are, albeit to differing extents, activated by fatty acids and derivatives, PPAR-alpha binds the hypolipidemic fibrates. PPAR-alpha activation mediates changes in lipoprotein metabolism. Moreover, PPAR-alpha activators increase hepatic uptake and esterification of free fatty acids, in addition to increasing mitochondrial free fatty acid uptake and the resulting free fatty acid oxidation. The effect of fibrates on the metabolism of triglyceride-rich lipoproteins is due to a PPAR-alpha-dependent stimulation of lipoprotein lipase and of apolipoprotein (apo)A-V and to an inhibition of apoC-III expression, whereas the increase in plasma HDL-cholesterol depends partly on an overexpression of apoA-I and apoA-II. PPARs are also expressed in atherosclerotic lesions.

Copyright 2006 Prous Science