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

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

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

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, LXRα-, LXRβ-, and LXRα/β-deficient mice. Our data expose differential regulatory patterns for Cyp2b10 and Cyp3a11 dependent on the expression of LXR iso forms 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.

Original languageEnglish (US)
Pages (from-to)1633-1642
Number of pages10
JournalJournal of lipid research
Volume46
Issue number8
DOIs
StatePublished - Aug 2005

Keywords

  • Constitutive androstane receptor
  • Cytochrome P450 2ab10
  • Cytochrome P450 3a11
  • Liver X receptor
  • Metabolism
  • Pregnane X receptor

ASJC Scopus subject areas

  • Endocrinology

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