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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2731.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

The RXR Agonist Bexarotene Improves Cholesterol Homeostasis and Inhibits Atherosclerosis Progression in a Mouse Model of Mixed Dyslipidemia

Fanny Lalloyer; Catherine Fiévet; Sophie Lestavel; Gérard Torpier; Jelske van der Veen; Véronique Touche; Stéphanie Bultel; Saïd Yous; Folkert Kuipers; Réjane Paumelle; Jean-Charles Fruchart; Bart Staels; Anne Tailleux

From Institut Pasteur de Lille (F.L., C.F., S.L., G.T., V.T., S.B., R.P., J.-C.F., B.S., A.T.), Département d’Athérosclérose, Lille, France; Inserm (F.L., C.F., S.L., G.T., V.T., S.B., R.P., J.-C.F., B.S., A.T.), U545, Lille, France; Université de Lille 2 (F.L., C.F., S.L., G.T., V.T., S.B., R.P., J.-C.F., B.S., A.T.), Lille, France; Center for Liver, Digestive, and Metabolic Disease (J.v.d.V., F.K.), University Medical Center Groningen, Groningen, The Netherlands; Institut de Chimie Pharmaceutique Albert Lespagnol (S.Y.), Université de Lille 2, Lille, France.

Correspondence to Anne Tailleux, Inserm U545, Institut Pasteur de Lille, 1 rue du Professeur Calmette, F-59019 Lille, France. E-mail Anne.Tailleux{at}pasteur-lille.fr

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.

Conclusion— 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.

In human apolipoprotein E2-knockin mice, the rexinoid bexarotene inhibits atherosclerotic lesion development in association with decreased intestinal cholesterol absorption, resulting in lower circulating atherogenic lipoprotein concentrations. Bexarotene enhances the capacity of macrophages to efflux cellular lipids, whereas it has only modest effects on inflammation in the vascular wall.

Key Words: atherosclerosis • cholesterol homeostasis • intestinal cholesterol absorption • rexinoid • triglycerides

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