• Open Access

Yes-associated protein regulates the hepatic response after bile duct ligation

Authors

  • Haibo Bai,

    1. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD
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    • These authors contributed equally to this work.

  • Nailing Zhang,

    1. Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD
    2. Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD
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    • These authors contributed equally to this work.

  • Yang Xu,

    1. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD
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  • Qian Chen,

    1. Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD
    2. Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD
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  • Mehtab Khan,

    1. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD
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  • James J. Potter,

    1. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
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  • Suresh K. Nayar,

    1. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD
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  • Toby Cornish,

    1. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD
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  • Gianfranco Alpini,

    1. Department of Medicine and Scott & White Digestive Disease Research Center, Texas A&M Health Science Center, College of Medicine, and Scott & White Hospital, and Research Service, Central Texas Veterans Health Care System, Temple, TX
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  • Steven Bronk,

    1. Division of Gastroenterology and Hepatology, Mayo Clinic School of Medicine, Rochester, MN
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  • Duojia Pan,

    Corresponding author
    1. Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD
    2. Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD
    • Duojia Pan, Johns Hopkins University, PCTB Room 714A, 725 N. Wolfe Street, Baltimore, MD 21205===

      Robert A. Anders, Johns Hopkins University, CRBII Room 346, 1550 Orleans Street, Baltimore, MD 21231===

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    • fax:410-502-3177

  • Robert A. Anders

    Corresponding author
    1. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD
    • Duojia Pan, Johns Hopkins University, PCTB Room 714A, 725 N. Wolfe Street, Baltimore, MD 21205===

      Robert A. Anders, Johns Hopkins University, CRBII Room 346, 1550 Orleans Street, Baltimore, MD 21231===

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    • fax: 410-614-0671


  • Potential conflict of interest: Nothing to report.

Abstract

Human chronic cholestatic liver diseases are characterized by cholangiocyte proliferation, hepatocyte injury, and fibrosis. Yes-associated protein (YAP), the effector of the Hippo tumor-suppressor pathway, has been shown to play a critical role in promoting cholangiocyte and hepatocyte proliferation and survival during embryonic liver development and hepatocellular carcinogenesis. Therefore, the aim of this study was to examine whether YAP participates in the regenerative response after cholestatic injury. First, we examined human liver tissue from patients with chronic cholestasis. We found more-active nuclear YAP in the bile ductular reactions of primary sclerosing cholangitis and primary biliary cirrhosis patient liver samples. Next, we used the murine bile duct ligation (BDL) model to induce cholestatic liver injury. We found significant changes in YAP activity after BDL in wild-type mice. The function of YAP in the hepatic response after BDL was further evaluated with liver-specific Yap conditional deletion in mice. Ablating Yap in the mouse liver not only compromised bile duct proliferation, but also enhanced hepatocyte necrosis and suppressed hepatocyte proliferation after BDL. Furthermore, primary hepatocytes and cholangiocytes isolated from Yap-deficient livers showed reduced proliferation in response to epidermal growth factor in vitro. Finally, we demonstrated that YAP likely mediates its biological effects through the modulation of Survivin expression. Conclusion: Our data suggest that YAP promotes cholangiocyte and hepatocyte proliferation and prevents parenchymal damage after cholestatic injury in mice and thus may mediate the response to cholestasis-induced human liver disease. (HEPATOLOGY 2012;56:1097–1107)

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