Hepatocyte specific expression of an oncogenic variant of β-catenin results in cholestatic liver disease
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Ursula J. Lemberger1,2,3, Claudia D. Fuchs3, Matthias Karer1, Stefanie Haas1, Tatjana Stojakovic4, Christian Schöfer5, Hanns-Ulrich Marschall6, Fritz Wrba2, Makoto M. Taketo7, Gerda Egger2, Michael Trauner3, Christoph H. Österreicher1
1Institute of Pharmacology, Medical University of Vienna, Vienna, Austria
2Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria
3Hans Popper Laboratory for Molecular Hepatology, Department of Internal Medicine, Medical University of Vienna, Vienna, Austria
4Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
5Department of Cell and Developmental Biology, Medical University of Vienna, Vienna, Austria
6Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
7Division of Experimental Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Christoph H. Österreicher, email: [email protected]
Keywords: β-catenin, bile acids, cholestasis, biliary fibrosis, liver cancer
Received: April 03, 2016 Accepted: September 26, 2016 Published: November 23, 2016
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.
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 (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.
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