Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor
- Thierry Claudel*,†,
- Mark D. Leibowitz*,†,‡,
- Catherine Fiévet*,†,
- Anne Tailleux*,
- Brandee Wagner§,
- Joyce J. Repa¶,
- Gérard Torpier*,
- Jean-Marc Lobaccaro¶,
- James R. Paterniti‡,
- David J. Mangelsdorf¶,
- Richard A. Heyman‡,§, and
- Johan Auwerx‖,**
- *Département 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 Illkirch, France
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Communicated by David L. Garbers, University of Texas Southwestern Medical Center, Dallas, TX (received for review December 5, 2000)
Abstract
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.
Footnotes
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↵ † T.C., M.D.L., and C.F. contributed equally to this work.
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↵ ** To whom reprint requests should be addressed at: Institut de Génétique et Biologie Moléculaire et Cellulaire, Centre National de la Recherché Scientifique/INSERM/ULP, 1 Rue Laurent Fries, 67404 Illkirch, France. E-mail: auwerx{at}igbmc.u-strasbg.fr.
- Abbreviations:
- RXR,
- retinoid X receptor;
- LXR,
- liver X receptor;
- ABC-1,
- ATP-binding cassette protein 1;
- PPAR,
- peroxisome proliferator-activated receptor;
- LDL,
- low-density lipoprotein;
- HDL,
- high-density lipoprotein
- Copyright © 2001, The National Academy of Sciences
