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

• Type of Material: Article
• Authors: Fanghui Chen, Nanjing Agricultural University; Le Sheng, Nanjing Agricultural University; Tianci Zhou, Nanjing Agricultural University; Li Yan, Linyi People Hospital; Reid Loveless, Augusta University; Honglin Li, Augusta University; Yong Teng, Emory University; Yong yafei Cai, Nanjing Agricultural University
• Language: English
• Date: 2023-05-03
• Publisher: BMC
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2023
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s13046-023-02681-6
• Title of Journal or Parent Work: JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
• Volume: 42
• Issue: 1
• Start Page: 110
• End Page: 110
• Grant/Funding Information: This work was supported by NSFC grant (No. 31970413 to YC), Start-up grant from Nanjing Agricultural University (No. 804090 to YC), Winship Invest$ Team Science Award (to YT) and P30CA138292 (to Winship Cancer Institute). Research reported in this publication was also supported in part by Imagine, Innovate and Impact (I3) from the Emory School of Medicine, a gift from Woodruff Fund Inc., and through the Georgia CTSA NIH award (UL1-TR002378).
• Keywords: Science & Technology; HCC; RISK; ENDOPLASMIC-RETICULUM STRESS; PATHWAY; Oncology; Hepatic fibrosis; Fatty liver; Ufl1; HEPATOCELLULAR-CARCINOMA; CELLS; Ufbp1; UNFOLDED PROTEIN RESPONSE; MICE; mTOR; Life Sciences & Biomedicine
• Research Categories: Health Sciences, Oncology; Engineering, Biomedical

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 Ufl1 Δ/Δhep and Ufbp1 Δ/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: Ufl1 Δ/Δhep or Ufbp1 Δ/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 Ufl1 Δ/Δhep and Ufbp1 Δ/Δhep mice developed spontaneous hepatocellular carcinoma (HCC) by 14 months of age. Moreover, Ufl1 Δ/Δhep and Ufbp1 Δ/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.