Z Gastroenterol 2015; 53 - A1_5
DOI: 10.1055/s-0035-1567935

A disintegrin and metalloprotease 10 (ADAM10) is a central regulator of liver tissue homeostasis

M Müller 1, S Wetzel 1, J Köhn-Gaone 2, K Chalupsky 3, R Lüllmann-Rauch 4, R Barikbin 5, B Wöhner 1, G Tiegs 5, S Rose-John 1, R Sedlacek 3, JEE Tirnitz-Parker 6, P Saftig 1, D Schmidt-Arras 1
  • 1Christian-Albrechts-University, Institute of Biochemistry, Kiel, Germany
  • 2Curtin University, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Faculty of Health Sciences, Bentley, Australia
  • 3Institute of Molecular Genetics of the ASCR, Laboratory of Transgenic Models of Disease, Prague, Czech Republic
  • 4Christian-Albrechts-University, Institute of Anatomy, Kiel, Germany
  • 5University Medical Center Hamburg-Eppendorf, Institute of Experimental Immunology and Hepatology, Hamburg, Germany
  • 6University of Wester Australia, School of Biomedicien, Freemantle, Australia

A Disintegrin And Metalloprotease (ADAM) 10 exerts essential roles during organ development and tissue integrity in many organs. However, only little is known about its implication in liver tissue physiology. We therefore generated mice deficient for Adam10 in hepatocytes, cholangiocytes and liver progenitor cells. While biliary tree formation and bile canaliculi morphology was normal in ADAM10Δhep/Δch animals, we observed areas with hepatocyte necrosis. This correlated with an impaired expression of bile acid transporters. Decreased numbers of necrotic areas in 15-week old ADAM10Δhep/Δch mice were clear evidence for on-going regenerative processes in ADAM10-deficient livers. Interestingly, we observed a strongly augmented ductular reaction that was accompanied by activation of hepatic stellate cells in 15-week old ADAM10Δhep/Δch mice, resulting in fulminant liver fibrosis. We show in cell-based assays that lack of ADAM10 in liver progenitor cells leads to enhanced c-Met signalling.

In contrast to its role in other tissues, ADAM10 is dispensable for the Notch2-dependent biliary tree formation. However, our data demonstrate that ADAM10 is a central regulator of murine liver tissue homeostasis by regulating bile acid transporter expression and liver progenitor cell activation. As aberrant activation of liver progenitor cells is often found in chronic liver disease, ADAM10 may be considered a potential pharmaceutical target for the treatment of chronic liver disease.

Corresponding author: Schmidt-Arras, Dirk

E-Mail: darras@biochem.uni-kiel.de