Pleiotropic actions of peroxisome proliferator-activated receptors in lipid metabolism and atherosclerosis.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors activated by fatty acids and derivatives. Although PPARalpha mediates the hypolipidemic action of fibrates, PPARgamma is the receptor for the antidiabetic glitazones. PPARalpha is highly expressed in tissues such as liver, muscle, kidney, and heart, where it stimulates the beta-oxidative degradation of fatty acids. PPARgamma is predominantly expressed in adipose tissues, where it promotes adipocyte differentiation and lipid storage. PPARbeta/delta is expressed in a wide range of tissues, and recent findings indicate a role for this receptor in the control of adipogenesis. Pharmacological and gene-targeting studies have demonstrated a physiological role for PPARs in lipid and lipoprotein metabolism. PPARalpha controls plasma lipid transport by acting on triglyceride and fatty acid metabolism and by modulating bile acid synthesis and catabolism in the liver. All 3 PPARs regulate macrophage cholesterol homeostasis. By enhancing cholesterol efflux, they stimulate the critical steps of the reverse cholesterol transport pathway. As such, PPARs control plasma levels of cholesterol and triglycerides, which constitute major risk factors for coronary heart disease. Furthermore, PPARalpha and PPARgamma regulate the expression of key proteins involved in all stages of atherogenesis, such as monocyte and lymphocyte recruitment to the arterial wall, foam cell formation, vascular inflammation, and thrombosis. Thus, by regulating gene transcription, PPARs modulate the onset and evolution of metabolic disorders predisposing to atherosclerosis and exert direct antiatherogenic actions at the level of the vascular wall.