| First Author | Lemberger UJ | Year | 2018 |
| Journal | Oncotarget | Volume | 9 |
| Issue | 13 | Pages | 11243-11257 |
| PubMed ID | 29541410 | Mgi Jnum | J:298064 |
| Mgi Id | MGI:6457202 | Doi | 10.18632/oncotarget.24346 |
| Citation | Lemberger UJ, et al. (2018) Hepatocyte specific expression of an oncogenic variant of beta-catenin results in lethal metabolic dysfunction in mice. Oncotarget 9(13):11243-11257 |
| abstractText | Background: Wnt/beta-catenin signaling plays a crucial role in embryogenesis, tissue homeostasis, metabolism and malignant transformation of different organs including the liver. Continuous beta-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 beta-catenin in hepatocytes resulted in 100% mortality within 31 days after birth. Ctnnb1(CA)(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 Ctnnb1(CA)(hep) mice. Furthermore, carbohydrate metabolism was substantially disturbed in mutant mice. Conclusion: Continuous beta-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 beta-catenin signaling on liver biology we analyzed mice with hepatocyte specific expression of a dominant stable form of beta-catenin (Ctnnb1(CA)(hep) ) and their WT littermates by serum biochemistry, histology, electron microscopy, mRNA profiling and proteomic analysis of the liver. |
