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

Clinical and Administrative Pharmacy, University of Iowa, Iowa City, IA 52242

Corresponding Author: 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 hepatic bile acids and cholesterol metabolism. The goal of this study was to address potential effects of CAR on the metabolism of high density lipoprotein (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 apoA-I levels in both WT and HuAITg mice, but not CAR-/- mice. Both mouse apolipoprotein A-I and human apolipoprotein A-I were decreased by more than 40 % after TCPOBOP treatment, and kinetic studies revealed that production rate of HDL is reduced in TCPOBOP-treated, wild-type 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 down-regulation of apolipoprotein A-I gene expression.

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