Regulation of macrophage gene expression by peroxisome-proliferator-activated receptor gamma: implications for cardiovascular disease

The peroxisome-proliferator-activated receptor gamma is a member of the nuc lear receptor superfamily that functions as a key transcriptional regulator of cell differentiation and lipid metabolism. In addition, peroxisome-prol iferator-activated receptor gamma is now recognized to be the biological re ceptor for the thiazolidinedione class of antidiabetic drugs, which include s trogliiazone and rosiglitazone. Recent evidence indicates that peroxisome -proliferator-activated receptor gamma is expressed at high levels in macro phages, including the foam cells of atherosclerotic lesions. Oxidized low-d ensity lipoprotein, which plays a central role in lesion development, can a ctivate peroxisome-proliferator-activated receptor :, by providing the cell with oxidized fatty acid ligands of the receptor. The elucidation of a per oxisome-proliferator-activated receptor gamma signalling pathway in macroph ages provides a mechanism by which oxidized lipids may directly regulate ge ne expression in the context of the atherosclerotic lesion. A number of pot ential target genes for peroxisome-proliferator-activated receptor gamma in these cells have been identified. Some, such as the type B scavenger recep tor CD36 are induced by peroxisome-proliferator-activated receptor gamma li gands, 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 influe nce of these drugs on the risk of atherosclerosis. The net effect of peroxi some-proliferator-activated receptor gamma ligands on the atherogenic proce ss is likely to reflect a balance between local effects in the artery wall and systemic effects on lipid metabolism. Curr Opin Lipidol 10:485-490. (C) 1999 Lippincott Williams & Wilkins.