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

  • J Exp Clin Cancer Res. 2023 May 3;42(1):110. doi: 10.1186/s13046-023-02681-6.
Fanghui Chen  1  2 ,  Le Sheng  1 ,  Tianci Zhou  1 ,  Li Yan  3 ,  Reid Loveless  4 ,  Honglin Li  5 ,  Yong Teng  6  7 ,  Yafei Cai  8
Affiliations
  • 1. College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.
  • 2. Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, 30322, USA.
  • 3. Department of Radiation Oncology, Linyi People Hospital, Linyi, 276000, China.
  • 4. Department of Oral Biology and Diagnostic Sciences, Georgia Cancer Center, Augusta University, Augusta, GA, 30912, USA.
  • 5. Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.
  • 6. Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, 30322, USA. [email protected].
  • 7. Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA, 30322, USA. [email protected].
  • 8. College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China. [email protected].
PMID: 37131258 DOI: 10.1186/s13046-023-02681-6
Abstract

Background: Ufm1-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.

Methods: Hepatocyte-specific Ufl1Δ/Δhep and Ufbp1Δ/Δhep 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/GβL complex.

Results: Ufl1Δ/Δhep or Ufbp1Δ/Δhep 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 Ufl1Δ/Δhep and Ufbp1Δ/Δhep mice developed spontaneous hepatocellular carcinoma (HCC) by 14 months of age. Moreover, Ufl1Δ/Δhep and Ufbp1Δ/Δhep mice were more susceptible to HFD-induced fatty liver and DEN-induced HCC. Mechanistically, the Ufl1/Ufbp1 complex directly interacts with the mTOR/GβL complex and attenuates mTORC1 activity. Ablation of Ufl1 or Ufbp1 in hepatocytes dissociates them from the mTOR/GβL complex and activates oncogenic mTOR signaling to drive HCC development.

Conclusions: These 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.

Keywords
Fatty liver; HCC; Hepatic fibrosis; Ufl1/Ufbp1; mTOR.
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