title: A disintegrin and metalloprotease 10 (ADAM10) is a central regulator of murine liver tissue homeostasis.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Miryam
authors.initials: M
authors.lastname: Müller
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Wetzel
authors.affiliation: School of Biomedical Sciences, Curtin Health Innovation Research Institute, Faculty of Health Sciences, Curtin University, Bentley, Australia.
authors.forename: Julia
authors.initials: J
authors.lastname: Köhn-Gaone
authors.affiliation: Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the ASCR, Prague, Czech Republic.
authors.forename: Karel
authors.initials: K
authors.lastname: Chalupsky
authors.affiliation: Institute of Anatomy, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Renate
authors.initials: R
authors.lastname: Lüllmann-Rauch
authors.affiliation: Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Roja
authors.initials: R
authors.lastname: Barikbin
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany.|Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Juri
authors.initials: J
authors.lastname: Bergmann
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Birte
authors.initials: B
authors.lastname: Wöhner
authors.affiliation: Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the ASCR, Prague, Czech Republic.
authors.forename: Olga
authors.initials: O
authors.lastname: Zbodakova
authors.affiliation: Institute of Pathology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Ivo
authors.initials: I
authors.lastname: Leuschner
authors.affiliation: Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the ASCR, Prague, Czech Republic.|Laboratory of Integrative Biology, Institute of Molecular Genetics of the ASCR, Prague, Czech Republic.
authors.forename: Gregor
authors.initials: G
authors.lastname: Martin
authors.affiliation: Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Gisa
authors.initials: G
authors.lastname: Tiegs
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the ASCR, Prague, Czech Republic.
authors.forename: Radislav
authors.initials: R
authors.lastname: Sedlacek
authors.affiliation: 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.
authors.forename: Janina E E
authors.initials: JE
authors.lastname: Tirnitz-Parker
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schmidt-Arras
mesh_terms: D000072197:ADAM10 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D015536:Down-Regulation; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis; D008099:Liver / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009336:Necrosis; D051883:Receptor, Notch2 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C497765:Notch2 protein, mouse; D051883:Receptor, Notch2; C037643:bile acid binding proteins; D053829:Amyloid Precursor Protein Secretases; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse
keywords: ADAM10; Notch; Pathology Section; c-Met; hepatocyte differentiation; liver progenitor cell