Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis

Abstract

PPARalpha is a nuclear receptor that regulates liver and skeletal muscle lipid metabolism as well as glucose homeostasis. Acting as a molecular sensor of endogenous fatty acids (FAs) and their derivatives, this ligand-activated transcription factor regulates the expression of genes encoding enzymes and transport proteins controlling lipid homeostasis, thereby stimulating FA oxidation and improving lipoprotein metabolism. PPARalpha also exerts pleiotropic antiinflammatory and antiproliferative effects and prevents the proatherogenic effects of cholesterol accumulation in macrophages by stimulating cholesterol efflux. Cellular and animal models of PPARalpha help explain the clinical actions of fibrates, synthetic PPARalpha agonists used to treat dyslipidemia and reduce cardiovascular disease and its complications in patients with the metabolic syndrome. Although these preclinical studies cannot predict all of the effects of PPARalpha in humans, recent findings have revealed potential adverse effects of PPARalpha action, underlining the need for further study. This Review will focus on the mechanisms of action of PPARalpha in metabolic diseases and their associated vascular pathologies.

Figure 1

Metabolic actions of PPARα and potential pathophysiological consequences. The main effects of PPARα overexpression or of PPARα ligands in mice (denoted by a single asterisk) and in humans (denoted by a double asterisk) are shown. GSIS, glucose-stimulated insulin secretion.

Figure 2

PPARα and atherosclerosis. The effects of PPARα agonists in atherosclerosis are depicted for the most prominent cell type present in atherosclerotic lesions. NPC1 and 2, Niemann-Pick type C proteins 1 and 2; OxLDL, oxidized LDL; SR-BI, scavenger receptor BI; TF, tissue factor.