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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1488.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

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

From the University Lille Nord de France (F.L., B.G., S.L., S.Y., E.V., C.F., B.S., A.T.), Lille, France; Inserm, U545 (F.L., B.G., S.L., E.V., C.F., B.S., A.T.), Lille, France; UDSL (F.L., B.G., S.L., S.Y., E.V., C.F., B.S., A.T.), Lille, France; Institut Pasteur de Lille (F.L., B.G., S.L., E.V., C.F., B.S., A.T.), Lille, France; the Department of Biochemistry and Molecular Biology (T.A.P., S.M.), University of Southern Denmark, Odense; the Institut de Chimie Pharmaceutique Albert Lespagnol (S.Y.), Lille, France; the Department of Biosciences and Nutrition (J.-A.G.), Karolinska Institutet, Huddinge, Sweden; and the Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry (J.-A.G.), University of Houston, Tex.

Correspondence to Bart Staels, Inserm U545, Institut Pasteur de Lille, 1 rue du Professeur Calmette, F-59019 Lille, France. E-mail bart.staels{at}pasteur-lille.fr

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/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.

Key Words: retinoid-X-receptor • rexinoid • hypertriglyceridemia • liver-X-receptor • murine model • ChIP