The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity

Jeff L. Staudinger, Bryan Goodwin, Stacey A. Jones, Diane Hawkins-Brown, Kathleen I. MacKenzie, Anne LaTour, Yaping Liu, Curtis D. Klaassen, Kathleen K. Brown, John Reinhard, Timothy M. Willson, Beverly H. Koller, Steven A. Kliewer

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1007 Scopus citations

Abstract

The pregnane X receptor (PXR) is the molecular target for catatoxic steroids such as pregnenolone 16α-carbon itrile (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 7α-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.

Original languageEnglish (US)
Pages (from-to)3369-3374
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number6
DOIs
StatePublished - Mar 13 2001

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    Staudinger, J. L., Goodwin, B., Jones, S. A., Hawkins-Brown, D., MacKenzie, K. I., LaTour, A., Liu, Y., Klaassen, C. D., Brown, K. K., Reinhard, J., Willson, T. M., Koller, B. H., & Kliewer, S. A. (2001). The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proceedings of the National Academy of Sciences of the United States of America, 98(6), 3369-3374. https://doi.org/10.1073/pnas.051551698