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

Abstract

Background: 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.

Method: 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.

Results: 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.

Conclusion: 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.

Keywords: Inflammatory response; Liver fibrosis; MCP-1; Nrf2; Oxidative damage.