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The liver X-receptor alpha controls hepatic expression of the human bile acid–glucuronidating UGT1A3 enzyme in human cells and transgenic mice

Authors

  • Mélanie Verreault,

    1. Molecular Endocrinology and Oncology Research Center, CHUL Research Center and the Faculty of Pharmacy, Laval University, Québec, Canada
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  • Kathy Senekeo-Effenberger,

    1. Laboratory of Environmental Toxicology, Departments of Pharmacology, Chemistry and Biochemistry, University of California, San Diego, La Jolla, California
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  • Jocelyn Trottier,

    1. Molecular Endocrinology and Oncology Research Center, CHUL Research Center and the Faculty of Pharmacy, Laval University, Québec, Canada
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  • Jessica A. Bonzo,

    1. Laboratory of Environmental Toxicology, Departments of Pharmacology, Chemistry and Biochemistry, University of California, San Diego, La Jolla, California
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  • Julie Bélanger,

    1. Molecular Endocrinology and Oncology Research Center, CHUL Research Center and the Faculty of Pharmacy, Laval University, Québec, Canada
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  • Jenny Kaeding,

    1. Molecular Endocrinology and Oncology Research Center, CHUL Research Center and the Faculty of Pharmacy, Laval University, Québec, Canada
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  • Bart Staels,

    1. U545 INSERM, Departement d'Athérosclérose, Institut Pasteur de Lille and the Faculté de Pharmacie, Université de Lille II, Lille, France
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  • Patrick Caron,

    1. Molecular Endocrinology and Oncology Research Center, CHUL Research Center and the Faculty of Pharmacy, Laval University, Québec, Canada
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  • Robert H. Tukey,

    1. Laboratory of Environmental Toxicology, Departments of Pharmacology, Chemistry and Biochemistry, University of California, San Diego, La Jolla, California
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  • Olivier Barbier

    Corresponding author
    1. Molecular Endocrinology and Oncology Research Center, CHUL Research Center and the Faculty of Pharmacy, Laval University, Québec, Canada
    • CHUQ-CHUL Research Center, 2705 Laurier Boulevard, Québec (QUE) G1V 4G2, Canada
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    • fax: 418-654-2761


  • Potential conflict of interest: Nothing to report.

Abstract

Glucuronidation, an important bile acid detoxification pathway, is catalyzed by enzymes belonging to the UDP-glucuronosyltransferase (UGT) family. Among UGT enzymes, UGT1A3 is considered the major human enzyme for the hepatic C24-glucuronidation of the primary chenodeoxycholic (CDCA) and secondary lithocholic (LCA) bile acids. We identify UGT1A3 as a positively regulated target gene of the oxysterol-activated nuclear receptor liver X-receptor alpha (LXRα). In human hepatic cells and human UGT1A transgenic mice, LXRα activators induce UGT1A3 mRNA levels and the formation of CDCA-24glucuronide (24G) and LCA-24G. Furthermore, a functional LXR response element (LXRE) was identified in the UGT1A3 promoter by site-directed mutagenesis, electrophoretic mobility shift assays and chromatin immunoprecipitation experiment. In addition, LXRα is found to interact with the SRC-1α and NCoR cofactors to regulate the UGT1A3 gene, but not with PGC-1β. In conclusion, these observations establish LXRα as a crucial regulator of bile acid glucuronidation in humans and suggest that accumulation of oxysterols in hepatocytes during cholestasis favors bile acid detoxification as glucuronide conjugates. LXR agonists may be useful for stimulating both bile acid detoxification and cholesterol removal in cholestatic or hypercholesterolemic patients, respectively. (HEPATOLOGY 2006;44:368–378.)

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