title: Hepatocyte specific expression of an oncogenic variant of β-catenin results in cholestatic liver disease.
abstract: BACKGROUND
  The Wnt/β-catenin signaling pathway plays a crucial role in embryonic development, tissue homeostasis, wound healing and malignant transformation in different organs including the liver. The consequences of continuous β-catenin signaling in hepatocytes remain elusive.
  
  
  RESULTS
  Livers of Ctnnb1CA hep mice were characterized by disturbed liver architecture, proliferating cholangiocytes and biliary type of fibrosis. Serum ALT and bile acid levels were significantly increased in Ctnnb1CA hep mice. The primary bile acid synthesis enzyme Cyp7a1 was increased whereas Cyp27 and Cyp8b1 were reduced in Ctnnb1CA hep mice. Expression of compensatory bile acid transporters including Abcb1, Abcb4, Abcc2 and Abcc4 were significantly increased in Ctnnb1CA hep mice while Ntcp was reduced. Accompanying changes of bile acid transporters favoring excretion of bile acids were observed in intestine and kidneys of Ctnnb1CA hep mice. Additionally, disturbed bile acid regulation through the FXR-FGF15-FGFR4 pathway was observed in mice with activated β-catenin.
  
  
  METHODS
  Mice with a loxP-flanked exon 3 of the Ctnnb1 gene were crossed to Albumin-Cre mice to obtain mice with hepatocyte-specific expression of a dominant stable form of β-catenin (Ctnnb1CA hep mice). Ctnnb1CA hep mice were analyzed by histology, serum biochemistry and mRNA profiling.
  
  
  CONCLUSIONS
  Expression of a dominant stable form of β-catenin in hepatocytes results in severe cholestasis and biliary type fibrosis.
authors.affiliation: Institute of Pharmacology, Medical University of Vienna, Vienna, Austria.|Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.|Hans Popper Laboratory for Molecular Hepatology, Department of Internal Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Ursula J
authors.initials: UJ
authors.lastname: Lemberger
authors.affiliation: Hans Popper Laboratory for Molecular Hepatology, Department of Internal Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Claudia D
authors.initials: CD
authors.lastname: Fuchs
authors.affiliation: Institute of Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Matthias
authors.initials: M
authors.lastname: Karer
authors.affiliation: Institute of Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Haas
authors.affiliation: Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Stojakovic
authors.affiliation: Department of Cell and Developmental Biology, Medical University of Vienna, Vienna, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Schöfer
authors.affiliation: Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Hanns-Ulrich
authors.initials: HU
authors.lastname: Marschall
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Fritz
authors.initials: F
authors.lastname: Wrba
authors.affiliation: Division of Experimental Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Makoto M
authors.initials: MM
authors.lastname: Taketo
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Gerda
authors.initials: G
authors.lastname: Egger
authors.affiliation: Hans Popper Laboratory for Molecular Hepatology, Department of Internal Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
authors.affiliation: Institute of Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Christoph H
authors.initials: CH
authors.lastname: Österreicher
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics; D002779:Cholestasis / Q000209:etiology*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism*; D008105:Liver Cirrhosis, Biliary / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000502:physiology; D051176:beta Catenin / Q000502:physiology*
chemical_list: D001647:Bile Acids and Salts; C495267:CTNNB1 protein, mouse; D051176:beta Catenin; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse; D053493:Cholestanetriol 26-Monooxygenase; C506832:Cyp27a1 protein, mouse
keywords: bile acids; biliary fibrosis; cholestasis; liver cancer; β-catenin