J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M600282-JLR200 on November 6, 2006

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Journal of Lipid Research, Vol. 48, 373-384, February 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

PXR induces CYP27A1 and regulates cholesterol metabolism in the intestine

Tiangang Li, Wenling Chen and John Y. L. Chiang1

Department of Microbiology, Immunology, and Biochemistry, Northeastern Ohio Universities College of Medicine, Rootstown, OH 44272

Published, JLR Papers in Press, November 6, 2006.

1 To whom correspondence should be addressed. e-mail: jchiang{at}neoucom.edu

Mitochondrial sterol 27-hydroxylase (CYP27A1) catalyzes oxidative cleavage of the sterol side chain in the bile acid biosynthetic pathway in the liver and 27-hydroxylation of cholesterol in most tissues. Recent studies suggest that 27-hydroxycholesterol (27-HOC) activates liver orphan receptor {alpha} (LXR{alpha}) and induces the cholesterol efflux transporters ABCA1 and ABCG1 in macrophages. The steroid- and bile acid-activated pregnane X receptor (PXR) plays critical roles in the detoxification of bile acids, cholesterol metabolites, and xenobiotics. The role of CYP27A1 in the intestine is not known. This study investigated PXR and CYP27A1 regulation of cholesterol metabolism in the human intestinal cell lines Caco2 and Ls174T. A human PXR ligand, rifampicin, induced CYP27A1 mRNA expression in intestine cells but not in liver cells. Rifampicin induced CYP27A1 gene transcription, increased intracellular 27-HOC levels, and induced ABCA1 and ABCG1 mRNA expression only in intestine cells. A functional PXR binding site was identified in the human CYP27A1 gene. Chromatin immunoprecipitation assays revealed that rifampicin induced the PXR recruitment of steroid receptor coactivator 1 to CYP27A1 chromatin. Cholesterol loading markedly increased intracellular 27-HOC levels in intestine cells. Rifampicin, 27-HOC, and a potent LXR{alpha} agonist, T0901317, induced ABCA1 and ABCG1 protein expression and stimulated cholesterol efflux from intestine cells to apolipoprotein A-I and HDL. This study suggests an intestine-specific PXR/CYP27A1/LXR{alpha} pathway that regulates intestine cholesterol efflux and HDL assembly.

Supplementary key words bile acid synthesis • oxysterols • ATP binding cassette transporter A1 • ATP binding cassette transporter G1 • high density lipoprotein • liver orphan receptor • nuclear receptor • cholesterol efflux transporter • pregnane X receptor • sterol 27-hydroxylase

Abbreviations: apoA-I, apolipoprotein A-I; ChIP, chromatin immunoprecipitation; CYP27A1, sterol 27-hydroxylase; EMSA, electrophoretic mobility shift assay; 27-HOC, 27-hydroxycholesterol; LXR{alpha}, liver orphan receptor {alpha}; PPAR{gamma}, peroxisome proliferator-activated receptor {gamma}; PXR, pregnane X receptor; PXRE, pregnane X receptor response element; RXR, retinoid X receptor


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