Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 31, Issue 10, Pages 2232-U211Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.110.222497
Keywords
atherosclerosis; lipoproteins; constitutive androstane receptor
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Funding
- Universite de Bourgogne
- Conseil Regional de Bourgogne
- Institut National de la Sante et de la Recherche Medicale
- Agence Nationale de la Recherche
- Fondation de France
- National Institutes of Health [R01-DK46546, U19DK62434]
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Objective-The goal of this study was to determine the impact of the nuclear receptor constitutive androstane receptor (CAR) on lipoprotein metabolism and atherosclerosis in hyperlipidemic mice. Methods and Results-Low-density lipoprotein receptor-deficient (Ldlr(-/-)) and apolipoprotein E-deficient (ApoE(-/-)) mice fed a Western-type diet were treated weekly with the Car agonist 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) or the vehicle only for 8 weeks. In Ldlr(-/-) mice, treatment with TCPOBOP induced a decrease in plasma triglyceride and intermediate-density lipoprotein/low-density lipoprotein cholesterol levels (approximate to 30% decrease in both cases after 2 months, P<0.01). These mice also showed a significant reduction in the production of very-low-density lipoproteins associated with a decrease in hepatic triglyceride content and the repression of several genes involved in lipogenesis. TCPOBOP treatment also induced a marked increase in the very-low-density lipoprotein receptor in the liver, which probably contributed to the decrease in intermediate-density lipoprotein/low-density lipoprotein levels. Atherosclerotic lesions in the aortic valves of TCPOBOP-treated Ldlr(-/-) mice were also reduced (-60%, P<0.001). In ApoE(-/-) mice, which lack the physiological apoE ligand for the very-low-density lipoprotein receptor, the effect of TCPOBOP on plasma cholesterol levels and the development of atherosclerotic lesions was markedly attenuated. Conclusion-CAR is a potential target in the prevention and treatment of hypercholesterolemia and atherosclerosis. (Arterioscler Thromb Vasc Biol. 2011;31:2232-2239.)
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