Activation of peroxisome proliferator-activated receptor gamma and retinoid X receptor results in net depletion of cellular cholesteryl esters in macrophages exposed to oxidized lipoproteins

C. A. Argmann, C. G. Sawyez, C. J. McNeil, R. A. Hegele, M. W. Huff

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

Abstract

Objective - Peroxisome proliferator-activated receptor gamma (PPARγ), a ligand-activated transcription factor, has pleiotropic effects, including regulation of macrophage differentiation and lipid homeostasis. The PPARγ ligands, thiazolidinediones (TZDs), attenuate atherosclerosis in mice by uncertain mechanisms. The objective of this study was to determine whether activation of PPARγ or its obligate heterodimer, retinoid X receptor (RXR), modulates macrophage foam cell formation induced by oxidized (ox) lipoproteins. Methods and Results - Incubation of THP-1 macrophages with oxHTG-VLDL, oxREM, or oxLDL increased cellular cholesteryl ester over 6-fold. Preincubation with the TZD, ciglitazone, the RXR-specific ligand, 9-cis retinoic acid (9cRA) or the combination reduced CE mass accumulation by up to 65%. Ciglitazone and 9cRA increased CD36 mRNA (up to 4-fold); however, uptake of [125I]oxLDL was only modestly enhanced (up to 1.8-fold) becaues of a concomitant PPARγ:RXR-induced decrease in SRAI/II activity (up to 40%). This suggested that PPARγ:RXR activation inhibited cholesteryl ester accumulation by enhancing cholesterol efflux. Ciglitazone and 9cRA were found to increase the expression of ATP-binding cassette proteins A1 and G1, resulting in enhanced cholesterol efflux to lipoprotein-deficient serum, apoAI and HDL3. Conclusions - PPARγ and/or RXR activation inhibit foam cell formation through enhanced cholesterol efflux despite increased oxLDL uptake. These observations explain the reduced atherosclerosis in TZD-treated mice and may extend the therapeutic implications of these ligands.

Original languageEnglish
Pages (from-to)475-482
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume23
Issue number3
DOIs
StatePublished - 1 Mar 2003
Externally publishedYes

Keywords

  • Atherosclerosis
  • Macrophages
  • Oxidized lipoproteins
  • PPARγ

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