Int J Med Sci 2023; 20(4):557-565. doi:10.7150/ijms.77367 This issue Cite
1. Department of General Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
2. Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
3. Department of Respiratory and Critical Care Medicine, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430010, China
4. Department of Rheumatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
5. Department of Gastroenterology and Hepatology, Huangzhou District People's Hospital, Huanggang 438000, China
6. Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
Background and objectives: Hepatic stellate cell (HSC) activation is the cardinal factor due to the accumulation of extracellular matrix proteins during the development of liver fibrosis. The aim of the present study was to find new targets for developing drugs to treat liver fibrosis, by screening the key genes involved in the activation of hepatic stellate cells.
Methods: Differentially expressed genes were identified through TCGA database. RT-PCR, immunohistochemistry (IHC) assay, western blot, and ELISA were performed to evaluate the expression levels of FAT10 and fibrotic molecules. In vitro experiments were conducted to investigate the signaling pathways and biological functions of FAT10 in LX-2 cell lines.
Results: In the present study, expression profiles obtained from the Gene Expression Omnibus (GEO) were used to explore the different genes expression between HSCs treated with or without carbon tetrachloride (CCl4). Human leukocyte antigen (HLA)-F adjacent transcript 10 (FAT10) was selected for further investigations. In animal model of carbon tetrachloride-induced liver fibrosis, the expression of FAT10 on activated HSCs is upregulated. In vitro, silencing FAT10 reduced TGF-β1-induced ECM activation and accumulation in LX-2 cells, and also suppressed the inflammatory response of LX-2 cells. Further Transwell results suggested that knockdown of FAT10 could inhibit TGF-β1-induced LX-2 cell migration and invasion. Mechanistically, FAT10 promotes its fibrotic activity through regulating sirtuin 1 (SIRT1), with a concomitant activation of ECM.
Conclusions: These findings indicated an unexpected role of FAT10 in liver fibrosis development, suggesting that silencing FAT10 might represent a new strategy for the treatment of fibrotic liver diseases.
Keywords: FAT10, hepatic stellate cells, SIRT1, liver fibrosis, inflammation