Pregnane X receptor prevents hepatorenal toxicity from cholesterol metabolites

Junichiro Sonoda, Ling Wa Chong, Michael Downes, Grant D. Barish, Sally Coulter, Christopher Liddle, Chih Hao Lee, Ronald M. Evans*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

78 Scopus citations

Abstract

Efficient detoxification and clearance of cholesterol metabolites such as oxysterols, bile alcohols, and bile acids are critical for survival because they can promote liver and cardiovascular disease. We report here that loss of the nuclear xenobiotic receptor PXR (pregnane X receptor), a regulator of enterohepatic drug metabolism and clearance, results in an unexpected acute lethality associated with signs of severe hepatorenal failure when mice are fed with a diet that elicits accumulation of cholesterol and its metabolites. Induction of a distinct drug clearance program by a high-affinity ligand for the related nuclear receptor, the constitutive androstane receptor, does not overcome the lethality, indicating the unique requirement of PXR for detoxification. We propose that the PXR signaling pathway protects the body from toxic dietary cholesterol metabolites, and, by extension, PXR ligands may ameliorate human diseases such as cholestatic liver diseases and the associating acute renal failure.

Original languageEnglish (US)
Pages (from-to)2198-2203
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number6
DOIs
StatePublished - Feb 8 2005

ASJC Scopus subject areas

  • General

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