Regulation of peroxisome proliferator-activated receptor-gamma-mediated gene expression. A new mechanism of action for high density lipoprotein

• Published in: The Journal of biological chemistry 2002-06, Vol.277 (26), p.23582-23586
• Main Authors: Han, Jihong, Hajjar, David P, Zhou, Xiaoye, Gotto, Jr, Antonio M, Nicholson, Andrew C
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Adipocytes - drug effects; Adipocytes - physiology; Animals; Biological Transport; Carrier Proteins - genetics; Carrier Proteins - physiology; CD36 Antigens - genetics; Cell Differentiation - drug effects; Fatty Acid-Binding Protein 7; Fatty Acid-Binding Proteins; Gene Expression Regulation - drug effects; Lipoproteins, HDL - pharmacology; Mice; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - physiology; Neoplasm Proteins; Nerve Tissue Proteins; Phosphorylation; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - physiology; RNA, Messenger - analysis; Transcription Factors - genetics; Transcription Factors - physiology
• ISSN: 0021-9258
• DOI: 10.1074/jbc.M200685200

Cellular cholesterol content reflects a balance of lipid influx by lipoprotein receptors and endogenous synthesis and efflux to cholesterol acceptor particles. The beneficial effect of high density lipoprotein (HDL) in protecting against the development of cardiovascular disease is thought to be mediated predominately through its induction of cellular cholesterol efflux and "reverse cholesterol transport" from peripheral tissues to the liver. We tested the hypothesis that HDL could inhibit cellular lipid accumulation by modulating expression of peroxisome proliferator-activated receptor-gamma (PPARgamma)-responsive genes. To this end, we evaluated expression of two PPARgamma-responsive genes, CD36, a receptor for oxidized low density lipoprotein, and aP2, a fatty acid-binding protein. HDL decreased expression of macrophage CD36 and aP2 in a dose-dependent manner. HDL also decreased aP2 expression in fibroblasts, reduced accumulation of lipid, and slowed differentiation of fibroblasts into adipocytes. HDL stimulated mitogen-activated protein (MAP) kinase activity, and inhibition of CD36 expression was blocked by co-incubation with a MAP kinase inhibitor. HDL increased expression of PPARgamma mRNA and protein, induced translocation of PPARgamma from the cytoplasm to the nucleus, and increased PPARgamma phosphorylation. Our data demonstrate that despite induction and translocation of PPARgamma in response to HDL, MAP kinase-mediated phosphorylation of PPARgamma inhibited expression of PPARgamma-responsive genes and suggest mechanisms by which HDL may inhibit cellular lipid accumulation.