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Peroxisome Proliferator-activated Receptors in Atherosclerosis and Inflammation—An Update

Department of Pathology, GlaxoWellcome Inc, Research Triangle Park, North Carolina 27709, cse63957{at}GlaxoWellcome.com

Ronald D. Tyler

Department of Toxicology, Medicines Safety Evaluation, GlaxoWellcome Inc, Research Triangle Park, North Carolina 27709

Ruth M. Lightfoot

Department of Toxicology, Medicines Safety Evaluation, GlaxoWellcome Inc, Research Triangle Park, North Carolina 27709

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor subfamily of transcription factors with pleiotropic effects on intra- and extracellular lipid metabolism, glucose homeostasis, cell proliferation, control of inflammation, and atherosclerosis. Three PPARs, namely , , and have been identifi ed with distinct tissue distribution patterns and metabolic functions. PPAR- is predominantly expressed in brown adipose tissue, liver, kidney, duodenum, heart, skeletal muscle, and vascular endothelial cells and is involved in the control of lipoprotein metabolism, fatty acid oxidation, and the cellular uptake of fatty acids. PPAR- is highly expressed in brown and white adipose tissues and, to lesser extent, in large intestine, retina, and some parts of the immune system, and plays a critical role in adipocyte differentiation and fat deposition. PPAR- shows a widespread tissue distribution but its regulation and functions are not yet known. Considerable evidence indicates that PPARs (PPAR- and PPAR- ) have beneficial effects in infl ammatory diseases, including atherosclerosis, through regulation of cytokine production, adhesion molecule expression on the endothelial cells, fi brinolysis, and modulation of monocyte-derived macrophages. In this review, the general and specific roles of the PPAR isotypes and their implications in the control of vascular inflammation and atherosclerosis are discussed.

Key Words: Adipocyte differentiation • atherosclerosis • chemokines • cytokines • inflammation • nuclear receptors • peroxisome proliferator-activated receptors.

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