Regulation of lipid and lipoprotein metabolism by PPAR activators

The peroxisome proliferator-activated receptors (PPARs) are ligand-activate d transcription factors belonging to the nuclear hormone receptor superfami ly. PPAR alpha, the first identified PPAR family member, is principally exp ressed in tissues exhibiting high rates of beta-oxidation such as liver, ki dney, heart and muscle. PPAR gamma, on the other hand, is expressed at high levels in adipose tissue. PPARs are activated by dietary fatty acids and e icosanoids, as well as by pharmacological drugs, such as fibrates for PPAR alpha and glitazones for PPAR gamma. PPAR alpha mediates the hypolipidemic action of fibrates in the treatment of hypertriglyceridemia and hypoalphali poproteinemia. PPAR alpha is considered a major regulator of intra- and ext racellular lipid metabolism. Upon fibrate activation, PPAR alpha down-regul ates hepatic apolipoprotein C-III and increases lipoprotein lipase gene exp ression, key players in triglyceride metabolism. In addition, PPAR alpha ac tivation increases plasma HDL cholesterol via the induction of hepatic apol ipoprotein A-I and apolipoprotein A-II expression in humans. Glitazones exe rt a hypotriglyceridemic action via PPAR gamma-mediated induction of lipopr otein lipase expression in adipose tissue. PPARs play also a role in intrac ellular lipid metabolism by up-regulating the expression of enzymes involve d in conversion of fatty acids in acyl-coenzyme A esters, fatty acid entry into mitochondria and peroxisomal and mitochondrial fatty acid catabolism. These observations have provided the molecular basis leading to a better un derstanding of the mechanism of action of fibrates and glitazones on lipid and lipoprotein metabolism and identify PPARs as attractive targets for the rational design of more potent lipid-lowering drugs.