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Hepatocyte-Specific Deficiency of Nrf2 Exacerbates Carbon Tetrachloride-Induced Liver Fibrosis via Aggravated Hepatocyte Injury and Subsequent Inflammatory and Fibrogenic Responses
34 Pages Posted: 13 Dec 2019
More...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 macrophage in the progression of liver fibrosis, mice lacking Nrf2 specifically in hepatocytes [Nrf2(L)-KO] and macrophages [Nrf2(Mφ)-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.
Finding: 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(Mφ)-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.
Interpretation: 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 various toxic chemicals, suggesting that Nrf2 might be a valuable target for the intervention.
Funding Statement: National Natural Science Foundation of China (No. 81830099, 81573106, 81502841, 81402635, 81573187). Shenyang Municipal Bureau of Science and Technology Support Program for Young Innovation Scholar (RC180207), Liaoning Province Natural Science Foundation (20180530011).
Declaration of Interests: The authors declare that they have no conflict of interest.
Ethics Approval Statement: All animal protocols were approved by the Institutional Animal Care and Use Committees of China Medical University, and are in accordance with the US National Institutes of Health guidelines.
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