Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor
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Updated: Oct 9, 2026
Quantification of Atherosclerosis in Mice
Published on: June 12, 2019
T Claudel1, M D Leibowitz, C Fiévet
1Département d'Athérosclérose, Institut National de la Santé et de la Recherché Médicale (INSERM) U325, Institut Pasteur de Lille, 59019 Lille, France.
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)gamma and a dual agonist of both PPARalpha and PPARgamma 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 LXRalpha and beta 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.
Insights
Retinoid X receptor (RXR) agonists significantly reduced atherosclerosis development in mice. RXR/liver X receptor (LXR) activation promoted cholesterol efflux, suggesting potential therapeutic benefits for atherosclerosis.
Area of Science:
- Metabolic pathways
- Atherosclerosis research
- Nuclear receptor signaling
Background:
- Metabolic pathways are often regulated by retinoid X receptor (RXR) heterodimers.
- Dysregulation of these pathways contributes to atherosclerosis.
- Apolipoprotein E knockout mice are a standard model for studying atherosclerosis.
Purpose of the Study:
- To investigate the effects of RXR and its heterodimer activation on atherosclerosis.
- To explore the role of RXR/liver X receptor (LXR) heterodimers in cholesterol metabolism.
Main Methods:
- Administration of RXR agonist, peroxisome proliferator-activated receptor (PPAR)gamma ligand, and PPARalpha/gamma dual agonist to apolipoprotein E -/- mice.
- Analysis of atherosclerosis development.
- Assessment of ATP-binding cassette protein 1 (ABC-1) expression and cholesterol efflux in macrophages from wild-type and LXRalpha/beta double knockout mice.
Main Results:
- RXR agonist treatment drastically reduced atherosclerosis.
- PPAR agonists showed moderate inhibitory effects.
- RXR and LXR agonists increased ABC-1 expression and cholesterol efflux in wild-type macrophages, but not in LXR-deficient macrophages.
Conclusions:
- RXR activation has a significant protective effect against atherosclerosis.
- The RXR/LXR heterodimer's role in activating ABC-1-mediated cholesterol efflux may underlie the benefits of rexinoids.
- RXR/LXR agonists warrant further investigation for atherosclerosis prevention and treatment.
