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Journal of Lipid Research, Vol. 46, 1633-1642, August 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

LXR deficiency and cholesterol feeding affect the expression and phenobarbital-mediated induction of cytochromes P450 in mouse liver

Carmela Gnerre^1,*, Gertrud U. Schuster, Adrian Roth^*, Christoph Handschin, Lisen Johansson^,**, Renate Looser^*, Paolo Parini^,**, Michael Podvinec^*, Kirsten Robertsson, Jan-Åke Gustafsson and Urs A. Meyer^2,*

^* Division of Pharmacology/Neurobiology, Biozentrum of the University of Basel, CH-4056 Basel, Switzerland
Department of Biosciences at Novum, Karolinska Institutet, S-141 57 Huddinge, Sweden
Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Cell Biology, Harvard Medical School, Boston, MA 02115
^** Metabolism Unit, Center for Metabolism and Endocrinology, Department of Medicine, Novum, Karolinska Institutet at Huddinge University Hospital, S-141 86 Stockholm, Sweden

Published, JLR Papers in Press, June 1, 2005. DOI 10.1194/jlr.M400453-JLR200

¹ Present address of C. Gnerre: Actelion Pharmaceuticals Ltd., CH-4123 Allschwil, Switzerland.

² To whom correspondence should be addressed. e-mail: urs-a.meyer{at}unibas.ch

Metabolic transformation by the superfamily of cytochromes P450 (CYPs) plays an important role in the detoxification of xenobiotics such as drugs, environmental pollutants, and food additives. Endogenous substrates of CYPs include fatty acids, sterols, steroids, and bile acids. Induction of CYPs via transcriptional activation by substrates and other xenobiotics is an important adaptive mechanism that increases the organism's defense capability against toxicity. Numerous in vivo and in vitro data have highlighted the concept that the molecular mechanism of hepatic drug induction is linked to endogenous regulatory pathways. In particular, in vitro data suggest that oxysterols via the liver X receptor (LXR) inhibit phenobarbital (PB)-mediated induction of CYPs. To study the link between LXR, cholesterol homeostasis, and drug induction in vivo, we designed experiments in wild-type, LXR-, LXRß-, and LXR/ß-deficient mice. Our data expose differential regulatory patterns for Cyp2b10 and Cyp3a11 dependent on the expression of LXR isoforms and on challenge of cholesterol homeostasis by excess dietary cholesterol.

Our results suggest that, in the mouse, liver cholesterol status significantly alters the pattern of expression of Cyp3a11, whereas the absence of LXR leads to an increase in PB-mediated activation of Cyp2b10.

Abbreviations: CAR, constitutive androstane receptor; CYP, cytochrome P450; CYP7A1, cholesterol 7-hydroxylase; DR4, direct repeat separated by four nucleotides; FXR, farnesoid X receptor; LXR, liver X receptor; MRP3, multidrug resistance-associated protein 3; PB, phenobarbital; PBRU, phenobarbital-responsive enhancer unit; PCN, pregnenolone 16-carbonitrile; PXR, pregnane X receptor; SREBP-1c, sterol-regulatory element binding protein 1c; TG, triglyceride; XREM, xenobiotic-responsive enhancer module

Supplementary key words liver X receptor • pregnane X receptor • constitutive androstane receptor • metabolism • cytochrome P450 3a11 • cytochrome P450 2b10

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