Rexinoid bexarotene modulates triglyceride but not cholesterol metabolism via gene-specific permissivity of the RXR/LXR heterodimer in the liver

Fanny Lalloyer, Thomas Åskov Pedersen, Barbara Gross, Sophie Lestavel, Saïd Yous, Emmanuelle Vallez, Jan Åke Gustafsson, Susanne Mandrup, Catherine Fiévet, Bart Staels, Anne Tailleux

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

OBJECTIVE-: Bexarotene (Targretin) is a clinically used antitumoral agent which exerts its action through binding to and activation of the retinoid-X-receptor (RXR). The most frequent side-effect of bexarotene administration is an increase in plasma triglycerides, an independent risk factor of cardiovascular disease. The molecular mechanism behind this hypertriglyceridemia remains poorly understood. METHODS AND RESULTS-: Using wild-type and LXRα/β-deficient mice, we show here that bexarotene induces hypertriglyceridemia and activates hepatic LXR-target genes of lipogenesis in an LXR-dependent manner, hence exerting a permissive effect on RXR/LXR heterodimers. Interestingly, RNA analysis and Chromatin Immunoprecipitation assays performed in the liver reveal that the in vivo permissive effect of bexarotene on the RXR/LXR heterodimer is restricted to lipogenic genes without modulation of genes controlling cholesterol homeostasis. CONCLUSION-: These findings demonstrate that the hypertriglyceridemic action of bexarotene occurs via the RXR/LXR heterodimer and show that RXR heterodimers can act with a selective permissivity on target genes of specific metabolic pathways in the liver.

Original languageEnglish (US)
Pages (from-to)1488-1495
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume29
Issue number10
DOIs
StatePublished - Oct 2009

Keywords

  • ChIP
  • Hypertriglyceridemia
  • Liver-X-receptor
  • Murine model
  • Retinoid-X-receptor
  • Rexinoid

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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