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.

• Authors: Hang Lyu, Huihui Wang, Lu Li, Jiayu Zhu, Feng Chen, Yannan Chen, Cuijie Liu, Jingqi Fu, Bei Yang, Qiang Zhang, Yuanyuan Xu, Jingbo Pi
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 150 Pg. 136-147 (04 2020) ISSN: 1873-4596 [Electronic] United States
• PMID: 32112813 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• NF-E2-Related Factor 2
• Carbon Tetrachloride

Topics

• Animals
• Carbon Tetrachloride (toxicity)
• Chemical and Drug Induced Liver Injury (genetics, pathology)
• Hepatocytes (pathology)
• Liver (pathology)
• Liver Cirrhosis (chemically induced, genetics, pathology)
• Mice
• NF-E2-Related Factor 2 (genetics)