The RXR agonist bexarotene improves cholesterol homeostasis and inhibits atherosclerosis progression in a mouse model of mixed dyslipidemia.
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Lalloyer F, Fievet C, Lestavel S, Torpier G, van der Veen J, Touche V, Bultel S, Yous S, Kuipers F, Paumelle R, Fruchart JC, Staels B, Tailleux A
The RXR agonist bexarotene improves cholesterol homeostasis and inhibits atherosclerosis progression in a mouse model of mixed dyslipidemia.
Arterioscler Thromb Vasc Biol. 2006 Dec;26(12):2731-7. Epub 2006 Sep 28.
- PubMed ID
- 17008586 [ View in PubMed]
- Abstract
OBJECTIVE: The activity of the antitumoral agent bexarotene (Targretin, Bexarotene) depends on its binding to the nuclear retinoid-X receptor (RXR) and subsequent transcriptional regulation of target genes. Through RXR activation, bexarotene may modulate numerous metabolic pathways involved in atherosclerosis. Here, we investigated the effect of bexarotene on atherosclerosis progression in a dyslipidemic murine model, the human apolipoprotein E2 knockin mouse, that develops essentially macrophage-laden lesions. METHODS AND RESULTS: Atherosclerotic lesions together with different metabolic pathways involved in atherosclerosis were investigated in mice treated or not with bexarotene. Bexarotene protects from atherosclerosis development in mice, at least in part by improving the circulating cholesterol distribution profile likely via a marked decrease of dietary cholesterol absorption caused by modulation of intestinal expression of genes recently identified as major players in this process, Niemann-Pick-C1-Like1 (NPC1L1) and CD13. This atheroprotection appears despite a strong hypertriglyceridemia. Moreover, bexarotene treatment only modestly modulates inflammatory gene expression in the vascular wall, but markedly enhanced the capacity of macrophages to efflux cellular lipids. CONCLUSIONS: These data provide evidence of a favorable pharmacological effect of bexarotene on atherosclerosis despite the induction of hypertriglyceridemia, likely via a beneficial action on intestinal absorption and macrophage efflux.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Bexarotene Retinoic acid receptor RXR-alpha Protein Humans YesAgonistDetails Bexarotene Retinoic acid receptor RXR-beta Protein Humans YesAgonistDetails Bexarotene Retinoic acid receptor RXR-gamma Protein Humans YesAgonistDetails