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

Hang Lyu; Huihui Wang; Lu Li; Jiayu Zhu; Feng Chen; Yannan Chen; Cuijie Liu; Jingqi Fu; Bei Yang; Qiang Zhang; Yuanyuan Xu; Jingbo Pi

doi:10.1016/j.freeradbiomed.2020.02.015

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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

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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

Hang Lyu, Huihui Wang, Lu Li, Jiayu Zhu, Feng Chen, Yannan Chen, Cuijie Liu, Jingqi Fu, Bei Yang, Qiang Zhang, …

Free radical biology & medicine, Vol.150, pp.136-147

04/2020

DOI: 10.1016/j.freeradbiomed.2020.02.015

PMID: 32112813

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Abstract

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.

Inflammatory response

Liver fibrosis

MCP-1

Nrf2

Oxidative damage

Details

Title: Subtitle: Hepatocyte-specific deficiency of Nrf2 exacerbates carbon tetrachloride-induced liver fibrosis via aggravated hepatocyte injury and subsequent inflammatory and fibrogenic responses
Creators: Hang Lyu - School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China.
Huihui Wang - School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China.
Lu Li - School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China.
Jiayu Zhu - School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China.
Feng Chen - Department of Interventional Radiology, The First Affiliated Hospital of Shandong First Medical University, No. 16766 Jingshi Road, Lixia Area, Jinan, 250014, China.
Yannan Chen - School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China.
Cuijie Liu - School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China.
Jingqi Fu - School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China.
Bei Yang - China Medical University
Qiang Zhang - Emory University
Yuanyuan Xu - School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China.
Jingbo Pi - School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China.
Resource Type: Journal article
Publication Details: Free radical biology & medicine, Vol.150, pp.136-147
DOI: 10.1016/j.freeradbiomed.2020.02.015
PMID: 32112813
NLM abbreviation: Free Radic Biol Med
ISSN: 0891-5849
eISSN: 1873-4596
Publisher: Elsevier Inc
Grant note: DOI: 10.13039/501100001809, name: National Natural Science Foundation of China, award: 81830099, 81573106, 81502841, 81402635, 81573187, 81803008; DOI: 10.13039/501100007765, name: Shenyang Municipal Bureau of Science and Technology Support Program for Young Innovation Scholar, award: RC180207; DOI: 10.13039/501100005047, name: Liaoning Province Natural Science Foundation, award: 20180530011
Language: English
Date published: 04/2020
Academic Unit: Neurology
Record Identifier: 9984302210902771

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