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    The Nuclear Receptor PXR Functions as a Hepatic Lithocholic Acid Sensor

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    StaudingerJ_PNAS_98(6)3369.pdf (354.1Kb)
    Issue Date
    2001-03-13
    Author
    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
    Willson, Timothy M.
    Koller, Beverly H.
    Kliewer, Steven A.
    Publisher
    National Academy of Sciences
    Type
    Article
    Article Version
    Scholarly/refereed, publisher version
    Metadata
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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.
    Description
    This is the publisher's version, also available electronically from "http://www.pnas.org".
    URI
    http://hdl.handle.net/1808/17709
    DOI
    https://doi.org/10.1073/pnas.051551698
    Collections
    • Pharmacy Scholarly Works [280]
    Citation
    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

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    Lawrence, KS 66045
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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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