Regulation of macrophage gene expression by peroxisome-proliferator-activated receptor y

Abstract

The peroxisome-proliferator-activated receptor y is a member of the nuclear receptor superfamily that functions as a key transcriptional regulator of cell differentiation and lipid metabolism. In addition, peroxisome-proliferator-activated receptor y is now recognized to be the biological receptor for the thiazolidinedione class of antidiabetic drugs, which includes troglitazone and rosiglitazone. Recent evidence indicates that peroxisome-proliferator-activated receptor y is expressed at high levels in macrophages, including the foam cells of atherosclerotic lesions. Oxidized low-density lipoprotein, which plays a central role in lesion development, can activate peroxisome-proliferator-activated receptor y by providing the cell with oxidized fatty acid ligands of the receptor. The elucidation of a peroxisome-proliferator-activated receptor y signalling pathway in macrophages provides a mechanism by which oxidized lipids may directly regulate gene expression in the context of the atherosclerotic lesion. A number of potential target genes for peroxisome-proliferator-activated receptor y in these cells have been identified. Some, such as the type B scavenger receptor CD36 are induced by peroxisome-proliferator-activated receptor y ligands, whereas others, such as scavenger receptor type A, inducible nitric oxide synthetase and certain cytokines, are repressed. Given the widespread clinical use of thiazolidinediones, it is important to consider the influence of these drugs on the risk of atherosclerosis. The net effect of peroxisome-proliferator-activated receptor y ligands on the atherogenic process is likely to reflect a balance between local effects in the artery wall and systemic effects on lipid metabolism.