Faculty Collaboration Database

Activation of the constitutive androstane receptor decreases HDL in wild-type and human apoA-I transgenic mice. J Lipid Res 2008 Aug;49(8):1682-91

Date

04/29/2008

Pubmed ID

18441373

DOI

10.1194/jlr.M700374-JLR200

Scopus ID

2-s2.0-51449107194 (requires institutional sign-in at Scopus site)   36 Citations

Abstract

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.

Author List

Masson D, Qatanani M, Sberna AL, Xiao R, Pais de Barros JP, Grober J, Deckert V, Athias A, Gambert P, Lagrost L, Moore DD, Assem M

Author

Mahfoud Assem PharmD Associate Professor in the School of Pharmacy Administration department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Apolipoprotein A-I
Base Sequence
Cholesterol, HDL
Dietary Fats
Down-Regulation
Humans
Lipoproteins, HDL
Mice
Mice, Transgenic
Multidrug Resistance-Associated Proteins
Promoter Regions, Genetic
Pyridines
RNA, Messenger
Receptors, Cytoplasmic and Nuclear
Transcription Factors