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Published on: November 15, 2013

Pregnane X receptor prevents hepatorenal toxicity from cholesterol metabolites

Junichiro Sonoda1, Ling Wa Chong, Michael Downes

  • 1Howard Hughes Medical Institute and Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

Proceedings of the National Academy of Sciences of the United States of America
|January 27, 2005
PubMed

Insights

The nuclear receptor PXR (pregnane X receptor) is essential for detoxifying toxic cholesterol metabolites. Its absence causes severe liver and kidney failure in mice, highlighting PXR

Area of Science:

  • Hepatology
  • Toxicology
  • Molecular Biology

Background:

  • Cholesterol metabolites like oxysterols and bile acids can cause liver and cardiovascular disease.
  • Efficient detoxification pathways are crucial for preventing disease progression.

Purpose of the Study:

  • To investigate the role of the nuclear xenobiotic receptor PXR (pregnane X receptor) in the detoxification of cholesterol metabolites.
  • To determine if PXR is essential for survival when challenged with a diet causing cholesterol metabolite accumulation.

Main Methods:

  • Mice lacking the PXR gene were fed a diet designed to accumulate cholesterol metabolites.
  • Assessed survival rates and signs of hepatorenal failure in PXR-deficient mice.
  • Investigated the effect of a ligand for the related constitutive androstane receptor (CAR) on survival.

Main Results:

  • PXR-deficient mice exhibited acute lethality with severe hepatorenal failure when fed the cholesterol-rich diet.
  • Induction of drug clearance pathways by a CAR ligand did not prevent lethality, indicating a unique PXR role.
  • Loss of PXR uniquely impairs the detoxification of endogenous toxic sterols.

Conclusions:

  • The PXR signaling pathway is critical for protecting against toxic dietary cholesterol metabolites.
  • PXR is indispensable for preventing severe hepatorenal failure induced by sterol accumulation.
  • PXR ligands may offer therapeutic potential for cholestatic liver diseases and associated acute kidney injury.

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