Emerging roles of Notch signaling in liver disease

Authors

  • Fabian Geisler,

    Corresponding author
    1. Second Department of Internal Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
    • Address reprint requests to: Mario Strazzabosco, M.D., Ph.D., Liver Center, Department of internal Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520. E-mail: Mario.strazzabosco@yale.edu; fax: +1-203-785-7273 and Fabian Geisler, M.D., 2nd Department of Internal Medicine, Klinikum rechts der Isar, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany. E-mail: fabian.geisler@lrz.tum.de; fax: +49-89-41404958.

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  • Mario Strazzabosco

    Corresponding author
    1. Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT
    2. Department of Surgery and Interdisciplinary Medicine, University of Milano-Bicocca, Milan, Italy
    • Address reprint requests to: Mario Strazzabosco, M.D., Ph.D., Liver Center, Department of internal Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520. E-mail: Mario.strazzabosco@yale.edu; fax: +1-203-785-7273 and Fabian Geisler, M.D., 2nd Department of Internal Medicine, Klinikum rechts der Isar, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany. E-mail: fabian.geisler@lrz.tum.de; fax: +49-89-41404958.

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  • Potential conflict of interest: Nothing to report.

  • This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG grants GE 2289/1-2; to F.G.), a National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases award no. R01DK079005, an NIH grant (DK34989), Silvio O. Conte Digestive Diseases Research Core Centers, and by CARIPLO 2011-0470 and PRIN 2009ARYX4T_005 (to M.S.)

Abstract

This review critically discusses the most recent advances in the role of Notch signaling in liver development, homeostasis, and disease. It is now clear that the significance of Notch in determining mammalian cell fates and functions extends beyond development, and Notch is a major regular of organ homeostasis. Moreover, Notch signaling is reactivated upon injury and regulates the complex interactions between the distinct liver cell types involved in the repair process. Notch is also involved in the regulation of liver metabolism, inflammation, and cancer. The net effects of Notch signaling are highly variable and finely regulated at multiple levels, but also depend on the specific cellular context in which Notch is activated. Persistent activation of Notch signaling is associated with liver malignancies, such as hepatocellular carcinoma with stem cell features and intrahepatic cholangiocarcinoma. The complexity of the pathway provides several possible targets for agents able to inhibit Notch. However, further cell- and context-specific in-depth understanding of Notch signaling in liver homeostasis and disease will be essential to translate these concepts into clinical practice and be able to predict benefits and risks of evolving therapies. (Hepatology 2015;61:382–392)

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