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6566768 
Journal Article 
The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity 
Staudinger, JL; Goodwin, B; Jones, SA; Hawkins-Brown, D; Mackenzie, KI; Latour, A; Liu, Y; Klaassen, CD; Brown, KK; Reinhard, J; Willson, TM; Koller, BH; Kliewer, SA 
2001 
1 
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
EISSN: 1091-6490 
98 
6 
3369-3374 
English 
11248085 
WOS:000167521300079 
The pregnane X receptor (PXR) is the molecular target for catatoxic steroids such as pregnenolone 16alpha-carbonitrile (PCN), which induce cytochrome P450 3A (CYP3A) expression and protect the body from harmful chemicals. In this study, we demonstrate that PXR is activated by the toxic bile acid lithocholic acid (LCA) and its 3-keto metabolite. Furthermore, we show that PXR regulates the expression of genes involved in the biosynthesis, transport, and metabolism of bile acids including cholesterol 7alpha-hydroxylase (Cyp7a1) and the Na(+)-independent organic anion transporter 2 (Oatp2). Finally, we demonstrate that activation of PXR protects against severe liver damage induced by LCA. Based on these data, we propose that PXR serves as a physiological sensor of LCA, and coordinately regulates gene expression to reduce the concentrations of this toxic bile acid. These findings suggest that PXR agonists may prove useful in the treatment of human cholestatic liver disease.