Assignment No.

5 Peroxisome Proliferator-Activated Receptos PPARs

By Fakhruddin Babiker Ali

2013

PPARs are a group of orphan nuclear receptors comprising three subtypes; PPAR, PPAR/ and PPAR have the following features: 1- PPAR Promotes hepatic oxidation of fatty acids during fasting (catabolism). May have antiatherogenic eects by lowering both total and HDL-cholersterol levels. Expressed in liver, fat, and muscle. 2- PPAR/ Regulates cell growth and dierentiation via its eects on lipid metabolism and signaling in gut epithelium, brain, and placenta. May have tumor-promoting eects. Expressed in all tissues but especially in the colon, brain, kidney, and heart. 3- PPAR Enhances the storage of fatty acids in adipose tissue (lipogenesis) under anabolic (nonfasting) conditions. May have antidiabetic, antiatherogenic, and antitumor eects. Expressed mainly in the liver. Has three subtypes; PPAR1, PPAR2 and PPAR3. Ligands activating PPARs include the fatty acids phenylacetate and phenylbutyrate as well as: 1- PPAR ligands Fatty acids: linoleic acid, linolenic acid, phytanic acid. Eicosanoids: leukotriene B4, 8S-hydroxyeicosatetraenoic acid (8S-HETE). 2- PPAR/ ligands Eicosanoids: prostaglandin J2, 15-HETE. 3- PPAR Eicosanoids: prostaglandin I2 (prostacyclin). Also there are many therapeutically useful activators for PPARs, for instance the hypolipidimic drug Clofibrate which activates PPAR, thereby upregulating HDL-cholesterol and apoAI/AII while downregulating apoCIII and plasma triglyceride levels. Unlukily Clofibrate induced myopathies are mediated via PPAR activation in muscles. PPAR1 is expressed mainly in the liver, whereas PPAR2 primarily regulates the dierentiation of adipose tissue. Endogenous PPAR-activating ligands can inhibit aromatase activity (hence, estrogen biosynthesis) in human breast adipose tissue. Rosiglitazone has antitumor activity in adipose-derived mesenchymal tumors termed liposarcomas.