Liver X receptor α and farnesoid X receptor are major transcriptional regulators of OATP1B1

Authors

  • Henriette E. Meyer zu Schwabedissen,

    1. Division of Clinical Pharmacology, Department of Medicine, University of Western Ontario, London, Ontario, Canada
    2. Institute of Pharmacology, Department of Medicine, Ernst-Moritz Arndt-University of Greifswald, Greifswald, Germany
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  • Kerstin Böttcher,

    1. Institute of Pharmacology, Department of Medicine, Ernst-Moritz Arndt-University of Greifswald, Greifswald, Germany
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  • Amarjit Chaudhry,

    1. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN
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  • Heyo K. Kroemer,

    1. Institute of Pharmacology, Department of Medicine, Ernst-Moritz Arndt-University of Greifswald, Greifswald, Germany
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  • Erin G. Schuetz,

    1. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN
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  • Richard B. Kim

    Corresponding author
    1. Division of Clinical Pharmacology, Department of Medicine, University of Western Ontario, London, Ontario, Canada
    2. Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
    3. Lawson Health Research Institute, London, Ontario, Canada
    • Department of Medicine, LHSC-University Hospital, 339 Windermere Road, London, ON, N6A 5A5, Canada
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    • fax 1-519-663-3232


  • Potential conflict of interest: Nothing to report.

Abstract

Organic anion transporting polypeptide 1B1 (OATP1B1) is a liver-enriched transporter involved in the hepatocellular uptake of many endogenous molecules and several structurally divergent drugs in clinical use. Although OATP1B1 coding region polymorphisms are known to make an impact on substrate drug disposition in humans, little is known regarding the mechanisms underlying the transcriptional regulation of this transporter. In this study, we note that messenger RNA (mRNA) expression of OATP1B1 in a large human liver bank exhibited marked interindividual variability that was not associated with coding region polymorphisms. Accordingly, we hypothesized that such variability in expression is reflective of nuclear receptor-mediated transcriptional regulation of this transporter. We tested prototypical ligands for the nuclear receptors pregnane X receptor (PXR), constitutive androstane receptor (CAR), liver X receptor (LXR) α, and farnesoid X receptor (FXR) in a human hepatoma-derived cell line and noted induction of OATP1B1 mRNA when the cells were treated with LXRα or FXR ligands. To confirm a direct role for LXRα and FXR to OATP1B1 expression, we performed detailed promoter analysis and cell-based reporter gene assays resulting in the identification of two functional FXR response elements and one LXRα response element. The direct interaction between nuclear receptors with the identified response elements was assessed using chromatin immunoprecipitation assays. Using isolated primary human hepatocytes, we show that LXRα or FXR agonists, but not PXR or CAR agonists, are capable of OATP1B1 induction. Conclusion: We note that OATP1B1 transcriptional regulation is under dual nuclear receptor control through the oxysterol sensing LXRα and the bile acid sensor FXR. Accordingly, the interplay between OATP1B1 and nuclear receptors may play an important and heretofore unrecognized role during cholestasis, drug-induced liver injury, and OATP1B1 induction–related drug interactions. (HEPATOLOGY 2010)

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