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The Nuclear Receptor PXR Functions as a Hepatic Lithocholic Acid Sensor
Staudinger, Jeffrey Leonard Goodwin, Bryan Jones, Stacey A. Hawkins-Brown, Diane MacKenzie, Kathleen I. LaTour, Anne Liu, Yaping Klaassen, Curtis D. Brown, Kathleen K. Reinhard, John
Staudinger, Jeffrey Leonard
Goodwin, Bryan
Jones, Stacey A.
Hawkins-Brown, Diane
MacKenzie, Kathleen I.
LaTour, Anne
Liu, Yaping
Klaassen, Curtis D.
Brown, Kathleen K.
Reinhard, John
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Abstract
The pregnane X receptor (PXR) is the molecular target for catatoxic steroids such as pregnenolone 16α-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 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.
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This is the publisher's version, also available electronically from "http://www.pnas.org".
Date
2001-03-13
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National Academy of Sciences
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Staudinger, J. L., Goodwin, B., Jones, S. A., et al. (2001) The Nuclear Receptor PXR Functions as a Hepatic Lithocholic Acid Sensor. Proceedings National Academy of Sciences, 98(6), 3369-3374. http://www.dx.doi.org/10.1073/pnas.051551698