Thierry Claudel1, Mark D. Leibowitz1, Catherine Fiévet1, Anne Tailleux1, Brandee Wagner1, Joyce J. Repa1,2, Gérard Torpier1, Jean‐Marc A. Lobaccaro1, James R. Paterniti1, David J. Mangelsdorf3,1, Richard A. Heyman1, Johan Auwerx1,4
1Département d'Athérosclérose, Institut National de la Santé et de la Recherché Médicale (INSERM) U325, Institut Pasteur de Lille, 59019 Lille, France; Ligand Pharmaceuticals, San Diego, CA 92121; X-Ceptor Therapeutics, San Diego, CA 92121; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9050; and Institut de Génétique et Biologie Moléculaire et Cellulaire, Centre National de la Recherché Scientifique/INSERM/Université Louis Pasteur, 67404...
2Physiology
3Biochemistry,
4Universite de Strasbourg
Tóm tắt
A common feature of many metabolic pathways is their control by retinoid X receptor (RXR) heterodimers. Dysregulation of such metabolic pathways can lead to the development of atherosclerosis, a disease influenced by both systemic and local factors. Here we analyzed the effects of activation of RXR and some of its heterodimers in apolipoprotein E −/− mice, a well established animal model of atherosclerosis. An RXR agonist drastically reduced the development of atherosclerosis. In addition, a ligand for the peroxisome proliferator-activated receptor (PPAR)γ and a dual agonist of both PPARα and PPARγ had moderate inhibitory effects. Both RXR and liver X receptor (LXR) agonists induced ATP-binding cassette protein 1 (ABC-1) expression and stimulated ABC-1-mediated cholesterol efflux from macrophages from wild-type, but not from LXRα and β double −/−, mice. Hence, activation of ABC-1-mediated cholesterol efflux by the RXR/LXR heterodimer might contribute to the beneficial effects of rexinoids on atherosclerosis and warrant further evaluation of RXR/LXR agonists in prevention and treatment of atherosclerosis.
