Hepatocyte specific expression of an oncogenic variant of β-catenin results in cholestatic liver disease

// Ursula J. Lemberger 1, 2, 3 , Claudia D. Fuchs 3 , Matthias Karer 1 , Stefanie Haas 1 , Tatjana Stojakovic 4 , Christian Schofer 5 , Hanns-Ulrich Marschall 6 , Fritz Wrba 2 , Makoto M. Taketo 7 , Gerda Egger 2 , Michael Trauner 3 , Christoph H. Osterreicher 1 1 Institute of Pharmacology, Medical University of Vienna, Vienna, Austria 2 Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria 3 Hans Popper Laboratory for Molecular Hepatology, Department of Internal Medicine, Medical University of Vienna, Vienna, Austria 4 Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria 5 Department of Cell and Developmental Biology, Medical University of Vienna, Vienna, Austria 6 Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden 7 Division of Experimental Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan Correspondence to: Christoph H. Osterreicher, email: coesterr@gmail.com Keywords: β-catenin, bile acids, cholestasis, biliary fibrosis, liver cancer Received: April 03, 2016      Accepted: September 26, 2016      Published: November 23, 2016 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 Ctnnb1 CA 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 Ctnnb1 CA hep mice. The primary bile acid synthesis enzyme Cyp7a1 was increased whereas Cyp27 and Cyp8b1 were reduced in Ctnnb1 CA hep mice. Expression of compensatory bile acid transporters including Abcb1 , Abcb4 , Abcc2 and Abcc4 were significantly increased in Ctnnb1 CA hep mice while Ntcp was reduced. Accompanying changes of bile acid transporters favoring excretion of bile acids were observed in intestine and kidneys of Ctnnb1 CA hep mice. Additionally, disturbed bile acid regulation through the FXR-FGF15-FGFR4 pathway was observed in mice with activated β-catenin. Materials and 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 ( Ctnnb1 CA hep mice). Ctnnb1 CA 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.