Regulation of lipid and lipoprotein metabolism by PPAR activators

The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. PPAR alpha, the first identified PPAR family member, is principally expressed in tissues exhibiting high rates of beta-oxidation such as liver, kidney, 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 eicosanoids, 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 hypoalphalipoproteinemia. PPAR alpha is considered a major regulator of intra- and extracellular lipid metabolism. Upon fibrate activation, PPAR alpha down-regulates hepatic apolipoprotein C-III and increases lipoprotein lipase gene expression, key players in triglyceride metabolism. In addition, PPAR alpha activation increases plasma HDL cholesterol via the induction of hepatic apolipoprotein A-I and apolipoprotein A-II expression in humans. Glitazones exert a hypotriglyceridemic action via PPAR gamma-mediated induction of lipoprotein lipase expression in adipose tissue. PPARs play also a role in intracellular lipid metabolism by up-regulating the expression of enzymes involved 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 understanding 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.