Physiological and therapeutic roles of peroxisome proliferator-activated receptors.
The peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor isoforms, including PPARgamma, PPARalpha, and PPARdelta, encoded by different genes. PPARs are ligand-regulated transcription factors that control gene expression by binding to specific response elements (PPREs) within promoters. PPARs bind as heterodimers with a retinoid X receptor and, upon binding agonist, interact with cofactors increasing the rate of transcription initiation. The PPARs play a critical physiological role as lipid sensors and regulators of lipid metabolism. Natural ligands for the PPARs include fatty acids and eicosanoids. More potent synthetic PPAR ligands, including the fibrates and thiazolidinediones, are effective in the treatment of dyslipidemia and diabetes. Use of selective ligands led to the discovery of additional potential roles for the PPARs in pathological states, including atherosclerosis, inflammation, and hypertension. This review provides an overview of the molecular mechanisms of PPAR action and the involvement of the PPARs in the etiology and treatment of several chronic diseases.
Berger
Joel
J
Department of Metabolic Disorders-Diabetes, Merck Research Laboratories, PO Box 2000, Rahway, New Jersey 07065, USA. joel_berger@merck.com.
Wagner
John A
JA
D000818:Animals; D003920:Diabetes Mellitus / Q000188:drug therapy; D005786:Gene Expression Regulation; D006801:Humans; D006949:Hyperlipidemias / Q000188:drug therapy; D007333:Insulin Resistance; D008024:Ligands; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology* / Q000627:therapeutic use; D018168:Receptors, Retinoic Acid / Q000235:genetics; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology* / Q000627:therapeutic use
D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors