PPARα in atherosclerosis and inflammation

Peroxisome proliferator-activated receptor (PPAR)a is a nuclear receptor activated by natural ligands such as fatty acids as well as by synthetic ligands such as fibrates currently used to treat dyslipidemia. PPAR alpha regulates the expression of genes encoding proteins that are involved in lipid metabolism, fatty acid oxidation, and glucose homeostasis, thereby improving markers for atherosclerosis and insulin resistance. In addition, PPAR alpha exerts anti -inflammatory effects both in the vascular wall and the liver. Here we provide an over-view of the mechanisms through which PPARa affects the initiation and progression of atherosclerosis, with emphasis on the modulation of atherosclerosis-associated inflammatory responses. PPARa activation interferes with early steps in atherosclerosis by reducing leukocyte adhesion to activated endothelial cells of the arterial vessel wall and inhibiting subsequent transendothelial leukocyte migration. In later stages of atherosclerosis, evidence suggests activation of PPAR alpha inhibits the formation of macrophage foam cells by regulating expression of genes involved in reverse cholesterol transport, fort-nation of reactive oxygen species (ROS), and associated lipoprotein oxidative modification among others. Furthermore, PPAR alpha may increase the stability of atherosclerotic plaques and limit plaque thrombogenicity. These various effects may be linked to the generation of PPARa. ligands by endogenous mechanisms of lipoprotein metabolism. In spite of this dataset, other reports implicate PPAR alpha in responses such as hypertension and diabetic cardiomyopathy. Although some clinical trials data with fibrates suggest that fibrates may decrease cardiovascular events, other studies have been less clear, in terms of benefit. Independent of the clinical effects of currently used drugs purported to achieve PPARa, extensive data establish the importance of PPAR alpha in the transcriptional regulation of lipid metabolism, atherosclerosis, and inflammation. alpha 2007 Elsevier B.V. All rights reserved.