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

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 LXR alpha/beta-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. CONCLUSIONS: 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.
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https://www.hal.inserm.fr/inserm-00410108
Contributor : Marie-Hélène Derudas <>
Submitted on : Friday, January 8, 2010 - 11:40:24 AM
Last modification on : Friday, October 9, 2020 - 3:30:02 PM
Long-term archiving on: : Tuesday, September 18, 2012 - 12:56:34 PM

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Fanny Lalloyer, Thomas Åskov Pedersen, Barbara Gross, Sophie Lestavel, Saïd Yous, et al.. Rexinoid bexarotene modulates triglyceride but not cholesterol metabolism via gene-specific permissivity of the RXR/LXR heterodimer in the liver.. Arteriosclerosis, Thrombosis, and Vascular Biology, American Heart Association, 2009, 29 (10), pp.1488-95. ⟨10.1161/ATVBAHA.109.189506⟩. ⟨inserm-00410108⟩

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