Pregnane X Receptor Prevents Hepatorenal Toxicity from Cholesterol Metabolites

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...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2005-02, Vol.102 (6), p.2198-2203
Main Authors: Sonoda, Junichiro, Chong, Ling Wa, Downes, Michael, Barish, Grant D., Coulter, Sally, Liddle, Christopher, Lee, Chih-Hao, Evans, Ronald M.
Format: Article
Language:English
Subjects:
Animals
Bile acids
Bile Acids and Salts - blood
Biological Sciences
Biomarkers
Blood plasma
Cholesterol
Cholesterol metabolism
Cholesterol, Dietary - metabolism
Cholesterols
Gene Expression Profiling
Hepatorenal Syndrome - metabolism
Hepatorenal Syndrome - pathology
Humans
Hyperbilirubinemia - blood
Jaundice
Liver
Liver diseases
Male
Metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Oligonucleotide Array Sequence Analysis
Phenotype
Receptors
Receptors, Cytoplasmic and Nuclear - genetics
Receptors, Cytoplasmic and Nuclear - metabolism
Receptors, Steroid - genetics
Receptors, Steroid - metabolism
RNA
Rodents
Signal transduction
Signal Transduction - physiology
Survival Rate
Toxins
Transcription Factors - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0409481102