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

Fanny Lalloyer (1) , Thomas Åskov Pedersen (2) , Barbara Gross (1) , Sophie Lestavel (1) , Saïd Yous (3) , Emmanuelle Vallez (1) , Jan-Åke Gustafsson (4, 5) , Susanne Mandrup (2) , Catherine Fiévet (1) , Bart Staels (1) , Anne Tailleux (1)

1 Récepteurs nucléaires, lipoprotéines et athérosclérose
2 Department of Biochemistry and Molecular Biology
3 ICPAL - Institut de Chimie Pharmaceutique Albert Lespagnol
4 Department of Biosciences and Nutrition, Karolinska Institut
5 Department of Biology and Biochemistry

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.

Mots clés: Retinoid-X-Receptor; rexinoid; hypertriglyceridemia; Liver-X-Receptor; murine model; ChIP

Domaines: Biochimie, Biologie Moléculaire

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, 2009, 29 (10), pp.1488-95. ⟨10.1161/ATVBAHA.109.189506⟩. ⟨inserm-00410108⟩