Loss of Ufl1/Ufbp1 in hepatocytes promotes liver pathological damage and carcinogenesis through activating mTOR signaling

BackgroundUfm1-specific ligase 1 (Ufl1) and Ufm1-binding protein 1 (Ufbp1), as putative targets of ubiquitin-fold modifier 1 (Ufm1), have been implicated in several pathogenesis-related signaling pathways. However, little is known about their functional roles in liver disease.MethodsHepatocyte-specific Ufl1(Delta/Delta hep) and Ufbp1(Delta/Delta hep) mice were used to study their role in liver injury. Fatty liver disease and liver cancer were induced by high-fat diet (HFD) and diethylnitrosamine (DEN) administration, respectively. iTRAQ analysis was employed to screen for downstream targets affected by Ufbp1 deletion. Co-immunoprecipitation was used to determine the interactions between the Ufl1/Ufbp1 complex and the mTOR/G beta L complex.ResultsUfl1(Delta/Delta hep) or Ufbp1(Delta/Delta hep) mice exhibited hepatocyte apoptosis and mild steatosis at 2 months of age and hepatocellular ballooning, extensive fibrosis, and steatohepatitis at 6-8 months of age. More than 50% of Ufl1(Delta/Delta hep) and Ufbp1(Delta/Delta hep) mice developed spontaneous hepatocellular carcinoma (HCC) by 14 months of age. Moreover, Ufl1(Delta/Delta hep) and Ufbp1(Delta/Delta hep) mice were more susceptible to HFD-induced fatty liver and DEN-induced HCC. Mechanistically, the Ufl1/Ufbp1 complex directly interacts with the mTOR/G beta L complex and attenuates mTORC1 activity. Ablation of Ufl1 or Ufbp1 in hepatocytes dissociates them from the mTOR/G beta L complex and activates oncogenic mTOR signaling to drive HCC development.ConclusionsThese findings reveal the potential role of Ufl1 and Ufbp1 as gatekeepers to prevent liver fibrosis and subsequent steatohepatitis and HCC development by inhibiting the mTOR pathway.

Automated summary

Ufl1 and Ufbp1 play a role in preventing liver fibrosis, steatohepatitis and hepatocellular carcinoma (HCC) development by inhibiting the mTOR pathway.