Regulation of peroxisome proliferator-activated receptor-γ-mediated gene expression a new mechanism of action for high density lipoprotein

Jihong Han, David P. Hajjar, Xiaoye Zhou, Antonio M. Gotto, Andrew C. Nicholson

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

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-γ (PPARγ)-responsive genes. To this end, we evaluated expression of two PPARγ-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 PPARγ mRNA and protein, induced translocation of PPARγ from the cytoplasm to the nucleus, and increased PPARγ phosphorylation. Our data demonstrate that despite induction and translocation of PPARγ in response to HDL, MAP kinase-mediated phosphorylation of PPARγ inhibited expression of PPARγ-responsive genes and suggest mechanisms by which HDL may inhibit cellular lipid accumulation.

Original languageEnglish (US)
Pages (from-to)23582-23586
Number of pages5
JournalJournal of Biological Chemistry
Volume277
Issue number26
DOIs
StatePublished - Jun 28 2002

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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