Hepatocyte-specific deficiency of Nrf2 exacerbates carbon tetrachloride-induced liver fibrosis via aggravated hepatocyte injury and subsequent inflammatory and fibrogenic responses

• Published in: Free radical biology & medicine Vol. 150; pp. 136 - 147
• Main Authors: Lyu, Hang, Wang, Huihui, Li, Lu, Zhu, Jiayu, Chen, Feng, Chen, Yannan, Liu, Cuijie, Fu, Jingqi, Yang, Bei, Zhang, Qiang, Xu, Yuanyuan, Pi, Jingbo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2020
• Subjects: Inflammatory response; Liver fibrosis; MCP-1; Nrf2; Oxidative damage; Inflammatory response; MCP-1; Liver fibrosis; Nrf2; Oxidative damage
• ISSN: 0891-5849; 1873-4596; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2020.02.015

Liver fibrosis, in which hepatocyte damage and inflammatory response play critical roles, is a physiological response to chronic or iterative liver injury and can progress to cirrhosis over time. Nuclear factor E2-related factor 2 (Nrf2) is a master transcription factor that regulates oxidative and xenobiotic stress responses as well as inflammation. To ascertain the cell-specific roles of Nrf2 in hepatocytes and myeloid lineage cells in the progression of liver fibrosis, mice lacking Nrf2 specifically in hepatocytes [Nrf2(L)-KO] and myeloid lineage cells [Nrf2(M)-KO] were generated to evaluate carbon tetrachloride (CCl4)-induced liver injury, subsequent inflammation and fibrosis. In addition, mouse primary hepatocytes were used to investigate the underlying mechanisms. Nrf2-mediated antioxidant response in the liver is responsive to acute CCl4 exposure in mice. With repeated CCl4 administration, Nrf2(L)-KO, but not Nrf2(M)-KO, mice showed more severe liver fibrosis than Nrf2-LoxP control mice. In addition, in response to acute CCl4 exposure, Nrf2(L)-KO mice displayed aggravated liver injury, elevated lipid peroxidation and inflammatory response compared to control mice. In mouse primary hepatocytes, deficiency of Nrf2 resulted in more severe CCl4-induced lipid oxidation and inflammatory response. Deficiency of Nrf2 in hepatocytes sensitizes the cells to CCl4-induced oxidative damage and inflammatory response, which are initiator and enhancer of subsequent hepatic inflammation and fibrosis. Thus, Nrf2 is a critical determinant of liver injury and fibrosis in response to CCl4, suggesting that Nrf2 might be a valuable target for the intervention. [Display omitted] •CCl4 induces protein expression of Nrf2 and upregulates Nrf2 downstream genes in the liver.•Nrf2 in hepatocytes but not in myeloid lineage cells protects from CCl4-induced liver fibrosis.•Loss of Nrf2 sensitizes hepatocytes to CCl4-induced cytotoxicity and inflammatory response.