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, Johan Auwerx

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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.

Original languageEnglish (US)
Pages (from-to)2610-2615
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number5
DOIs
StatePublished - Feb 27 2001

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    Claudel, T., Leibowitz, M. D., Fiévet, C., Tailleux, A., Wagner, B., Repa, J. J., Torpier, G., Lobaccaro, J. M., Paterniti, J. R., Mangelsdorf, D. J., Heyman, R. A., & Auwerx, J. (2001). Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor. Proceedings of the National Academy of Sciences of the United States of America, 98(5), 2610-2615. https://doi.org/10.1073/pnas.041609298