Hepatocyte specific expression of an oncogenic variant of β-catenin results in lethal metabolic dysfunction in mice
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Ursula J. Lemberger1,2, Claudia D. Fuchs2, Christian Schöfer3, Andrea Bileck4, Christopher Gerner4, Tatjana Stojakovic5, Makoto M. Taketo6, Michael Trauner2, Gerda Egger1,7 and Christoph H. Österreicher8
1Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria
2Hans Popper Laboratory for Molecular Hepatology, Department of Internal Medicine, Medical University of Vienna, Vienna, Austria
3Department of Cell and Developmental Biology, Medical University of Vienna, Vienna, Austria
4Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria
5Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
6Division of Experimental Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
7Ludwig Boltzmann Institute Applied Diagnostics, Vienna, Austria
8Institute of Pharmacology, Medical University Vienna, Vienna, Austria
Keywords: Wnt signaling pathway; liver cancer; lipid metabolism; glucose metabolism; mitochondrial disorder
Received: August 31, 2017 Accepted: January 25, 2018 Published: January 30, 2018
Background: Wnt/β-catenin signaling plays a crucial role in embryogenesis, tissue homeostasis, metabolism and malignant transformation of different organs including the liver. Continuous β-catenin signaling due to somatic mutations in exon 3 of the Ctnnb1 gene is associated with different liver diseases including cancer and cholestasis.
Results: Expression of a degradation resistant form of β-catenin in hepatocytes resulted in 100% mortality within 31 days after birth. Ctnnb1CA hep mice were characterized by reduced body weight, significantly enlarged livers with hepatocellular fat accumulation around central veins and increased hepatic triglyceride content. Proteomics analysis using whole liver tissue revealed significant deregulation of proteins involved in fat, glucose and mitochondrial energy metabolism, which was also reflected in morphological anomalies of hepatocellular mitochondria. Key enzymes involved in transport and synthesis of fatty acids and cholesterol were significantly deregulated in livers of Ctnnb1CA hep mice. Furthermore, carbohydrate metabolism was substantially disturbed in mutant mice.
Conclusion: Continuous β-catenin signaling in hepatocytes results in premature death due to severe disturbances of liver associated metabolic pathways and mitochondrial dysfunction.
Methods: To investigate the influence of permanent β-catenin signaling on liver biology we analyzed mice with hepatocyte specific expression of a dominant stable form of β-catenin (Ctnnb1CA hep) and their WT littermates by serum biochemistry, histology, electron microscopy, mRNA profiling and proteomic analysis of the liver.
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