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.
Fichier principal
inserm-00410108_edited.pdf (835.34 Ko)
Télécharger le fichier
Data_supplement.pdf (76.38 Ko)
Télécharger le fichier
figures.pdf (39.8 Ko)
Télécharger le fichier
text_ATVB.pdf (115.66 Ko)
Télécharger le fichier
Origin : Files produced by the author(s)
Format : Other
Origin : Files produced by the author(s)
Origin : Files produced by the author(s)