Liver X receptor β and peroxisome proliferator-activated receptor δ regulate cholesterol transport in murine cholangiocytes

Authors

  • Xuefeng Xia,

    Corresponding author
    1. The Methodist Hospital Research Institute, Weill Cornell School of Medicine, Houston, TX
    2. The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
    • Xuefeng Xia, The Methodist Hospital Research Institute, 6670 Bertner Ave, R8-117, Houston, TX 77030

      Gene D. LeSage, Department of Internal Medicine, East Tennessee State University, VA Bldg. 1, Box 70622, Johnson City, TN 37614

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    • fax: 713-441-2178

  • Dongju Jung,

    1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
    Current affiliation:
    1. Dongju Jung is currently affiliated with the Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto, Japan
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  • Paul Webb,

    1. The Methodist Hospital Research Institute, Weill Cornell School of Medicine, Houston, TX
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  • Aijun Zhang,

    1. The Methodist Hospital Research Institute, Weill Cornell School of Medicine, Houston, TX
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  • Bin Zhang,

    1. The Methodist Hospital Research Institute, Weill Cornell School of Medicine, Houston, TX
    2. The Second Affiliated Hospital, Third Military Medical University, Chongqing, China
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  • Lifei Li,

    1. The Methodist Hospital Research Institute, Weill Cornell School of Medicine, Houston, TX
    2. The First Hospital, Lanzhou University, Lanzhou, Gansu, China
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  • Stephen D. Ayers,

    1. The Methodist Hospital Research Institute, Weill Cornell School of Medicine, Houston, TX
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  • Chiara Gabbi,

    1. Center for Nuclear Receptor and Cell Signaling, University of Houston, Houston TX
    2. Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
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  • Yoshiyuki Ueno,

    1. Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
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  • Jan-Åke Gustafsson,

    1. Center for Nuclear Receptor and Cell Signaling, University of Houston, Houston TX
    2. Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
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  • Gianfranco Alpini,

    1. Scott & White Digestive Diseases Research Center, Texas A&M Health Science Center College of Medicine, Temple, TX
    2. Division of Research, Central Texas Veterans Health Care System, Texas A&M Health Science Center College of Medicine, Temple, TX
    3. Department of Medicine, Texas A&M Health Science Center College of Medicine, Temple, TX
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  • David D. Moore,

    1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
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  • Gene D. LeSage

    Corresponding author
    1. Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN
    • Xuefeng Xia, The Methodist Hospital Research Institute, 6670 Bertner Ave, R8-117, Houston, TX 77030

      Gene D. LeSage, Department of Internal Medicine, East Tennessee State University, VA Bldg. 1, Box 70622, Johnson City, TN 37614

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    • fax: 423-439-6387


  • Potential conflict of interest: Nothing to report.

  • Supported by National Institutes of Health grants R01 DK53366 (to D. D. M.), RC4 DK90849 (to P. W.), and R01 DK54208 (to G. D. L.), and R01 DK062975 and a VA Merit Award (to G. A.).

Abstract

Nuclear receptors (NRs) play crucial roles in the regulation of hepatic cholesterol synthesis, metabolism, and conversion to bile acids, but their actions in cholangiocytes have not been examined. In this study, we investigated the roles of NRs in cholangiocyte physiology and cholesterol metabolism and flux. We examined the expression of NRs and other genes involved in cholesterol homeostasis in freshly isolated and cultured murine cholangiocytes and found that these cells express a specific subset of NRs, including liver X receptor (LXR) β and peroxisome proliferator-activated receptor (PPAR) δ. Activation of LXRβ and/or PPARδ in cholangiocytes induces ATP-binding cassette cholesterol transporter A1 (ABCA1) and increases cholesterol export at the basolateral compartment in polarized cultured cholangiocytes. In addition, PPARδ induces Niemann-Pick C1-like L1 (NPC1L1), which imports cholesterol into cholangiocytes and is expressed on the apical cholangiocyte membrane via specific interaction with a peroxisome proliferator-activated response element (PPRE) within the NPC1L1 promoter. Conclusion: We propose that (1) LXRβ and PPARδ coordinate NPC1L1/ABCA1-dependent vectorial cholesterol flux from bile through cholangiocytes and (2) manipulation of these processes may influence bile composition with important applications in cholestatic liver disease and gallstone disease, two serious health concerns for humans. (HEPATOLOGY 2012;56:2288–2296)

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