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Journal of Lipid Research, Vol. 49, 1682-1691, August 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Activation of the constitutive androstane receptor decreases HDL in wild-type and human apoA-I transgenic mice

David Masson^*,, Mohamed Qatanani, Anne Laure Sberna^*,, Rui Xiao, Jean Paul Pais de Barros^*,, Jacques Grober^*,, Valerie Deckert^*,, Anne Athias^*,, Philippe Gambert^*,, Laurent Lagrost^*,, David D. Moore and Mahfoud Assem^1,**

^* Institut National de la Santé et de la Recherche Médicale U866, Faculté de Médecine, BP 87900, 21079 Dijon Cedex, France
Institut Federatif de Recherche 100, Faculté de Médecine, BP 87900, 21079 Dijon Cedex, France
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030
^** Clinical and Administrative Pharmacy, College of Pharmacy, University of Iowa, Iowa City, IA 52242

This work was supported by the University of Iowa College of Pharmacy start-up funds, the Conseil Régional de Bourgogne, the Fondation de France, the Université de Bourgogne, and the Institut National de la Santé et de la Recherche Médicale.

Published, JLR Papers in Press, April 27, 2008.

¹To whom correspondence should be addressed. e-mail: mahfoud-assem{at}uiowa.edu

The nuclear hormone receptor constitutive androstane receptor (CAR, NR1I3) regulates detoxification of xenobiotics and endogenous molecules, and has been shown to be involved in the metabolism of hepatic bile acids and cholesterol. The goal of this study was to address potential effects of CAR on the metabolism of HDL particles, key components in the reverse transport of cholesterol to the liver. Wild-type (WT) mice, transgenic mice expressing human apolipoprotein A-I (HuAITg), and CAR-deficient (CAR^–/–) mice were treated with the specific CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP). CAR activation decreased HDL cholesterol and plasma apolipoprotein A-I (apoA-I) levels in both WT and HuAITg mice, but not CAR^–/– mice. Both mouse apoA-I and human apoA-I were decreased by more than 40% after TCPOBOP treatment, and kinetic studies revealed that the production rate of HDL is reduced in TCPOBOP-treated WT mice. In transient transfections, TCPOBOP-activated CAR decreased the activity of the human apoA-I promoter. Although loss of CAR function did not alter HDL levels in normal chow-fed mice, HDL cholesterol, apoA-I concentration, and apoA-I mRNA levels were increased in CAR^–/– mice relative to WT mice when both were fed a high-fat diet. We conclude that CAR activation in mice induces a pronounced decrease in circulating levels of plasma HDL, at least in part through downregulation of apoA-I gene expression.

Supplementary key words apolipoprotein A-I • bile acids • cholesterol • 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene

Abbreviations: apoA-I, apolipoprotein A-I; CAR, constitutive androstane receptor; CAR^–/– mice, CAR-deficient mice; CE, cholesteryl ester; FCR, fractional catabolic rate; FPLC, fast-protein liquid chromatography; FXR, farnesoid X receptor; HuAITg mice, transgenic mice expressing human apolipoprotein A-I; LXR, liver X receptor; PPAR peroxisome proliferator-activated receptor ; PXR, pregnane X receptor; TCPOBOP, 1,4-bis-[2-(3,5-dichloropyridyloxy)] benzene; WT, wild type

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