UNLABELLED: A Disintegrin And Metalloprotease (ADAM) 10 exerts essential roles during organ development and tissue integrity in different organs, mainly through activation of the Notch pathway. However, only little is known about its implication in liver tissue physiology. Here we show that in contrast to its role in other tissues, ADAM10 is dispensable for the Notch2-dependent biliary tree formation. However, we demonstrate that expression of bile acid transporters is dependent on ADAM10. Consequently, mice deficient for Adam10 in hepatocytes, cholangiocytes and liver progenitor cells develop spontaneous hepatocyte necrosis and concomitant liver fibrosis. We furthermore observed a strongly augmented ductular reaction in 15-week old ADAM10(Δhep/Δch) mice and demonstrate that c-Met dependent liver progenitor cell activation is enhanced. Additionally, liver progenitor cells are primed to hepatocyte differentiation in the absence of ADAM10. These findings show that ADAM10 is a novel central node controlling liver tissue homeostasis. HIGHLIGHTS: Loss of ADAM10 in murine liver results in hepatocyte necrosis and concomitant liver fibrosis. ADAM10 directly regulates expression of bile acid transporters but is dispensable for Notch2-dependent formation of the biliary system. Activation of liver progenitor cells is enhanced through increased c-Met signalling, in the absence of ADAM10. Differentiation of liver progenitor cells to hepatocytes is augmented in the absence of ADAM10.

Department of General and Thoracic Surgery University Hospital Schleswig Holstein Campus Kiel Kiel Germany

Institute of Anatomy Christian Albrechts University Kiel Germany

Institute of Biochemistry Christian Albrechts University Kiel Germany

Institute of Experimental Immunology and Hepatology University Medical Center Hamburg Eppendorf Hamburg Germany

Institute of Pathology University Hospital Schleswig Holstein Campus Kiel Kiel Germany

Laboratory of Integrative Biology Institute of Molecular Genetics of the ASCR Prague Czech Republic

Laboratory of Transgenic Models of Diseases Institute of Molecular Genetics of the ASCR Prague Czech Republic

School of Biomedical Sciences Curtin Health Innovation Research Institute Faculty of Health Sciences Curtin University Bentley Australia

School of Medicine and Pharmacology University of Western Australia Fremantle Australia

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