1. Immune‐Responsive Gene 1/Itaconate Activates Nuclear Factor Erythroid 2–Related Factor 2 in Hepatocytes to Protect Against Liver Ischemia–Reperfusion Injury
- Author
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Meihong Deng, Guang Fu, Zhao Lei, Chenxuan Yang, Hongbo Xu, Ping Sun, Patricia Loughran, Zhongjie Yi, Timothy R. Billiar, Shilai Li, Feizhou Huang, Wenbo Li, and Melanie J. Scott
- Subjects
0301 basic medicine ,Male ,Programmed cell death ,Carboxy-Lyases ,NF-E2-Related Factor 2 ,Anti-Inflammatory Agents ,medicine.disease_cause ,03 medical and health sciences ,Mice ,0302 clinical medicine ,medicine ,Animals ,Humans ,Hydro-Lyases ,Liver injury ,chemistry.chemical_classification ,Reactive oxygen species ,Hepatology ,Chemistry ,Succinates ,Original Articles ,Liver Injury/Regeneration ,medicine.disease ,Mice, Inbred C57BL ,Haematopoiesis ,Oxidative Stress ,030104 developmental biology ,medicine.anatomical_structure ,Liver ,Apoptosis ,Hepatocyte ,Reperfusion Injury ,Cancer research ,Hepatocytes ,030211 gastroenterology & hepatology ,Original Article ,Reperfusion injury ,Oxidative stress ,Signal Transduction - Abstract
Background and aims Itaconate, a metabolite of the tricarboxylic acid cycle, plays anti-inflammatory roles in macrophages during endotoxemia. The mechanisms underlying its anti-inflammatory roles have been shown to be mediated by the modulation of oxidative stress, an important mechanism of hepatic ischemia-reperfusion (I/R) injury. However, the role of itaconate in liver I/R injury is unknown. Approach and results We found that deletion of immune-responsive gene 1 (IRG1), encoding for the enzyme producing itaconate, exacerbated liver injury and systemic inflammation. Furthermore, bone marrow adoptive transfer experiments indicated that deletion of IRG1 in both hematopoietic and nonhematopoietic compartments contributes to the protection mediated by IRG1 after I/R. Interestingly, the expression of IRG1 was up-regulated in hepatocytes after I/R and hypoxia/reoxygenation-induced oxidative stress. Modulation of the IRG1 expression levels in hepatocytes regulated hepatocyte cell death. Importantly, addition of 4-octyl itaconate significantly improved liver injury and hepatocyte cell death after I/R. Furthermore, our data indicated that nuclear factor erythroid 2-related factor 2 (Nrf2) is required for the protective effect of IRG1 on mouse and human hepatocytes against oxidative stress-induced injury. Our studies document the important role of IRG1 in the acute setting of sterile injury induced by I/R. Specifically, we provide evidence that the IRG1/itaconate pathway activates Nrf2-mediated antioxidative response in hepatocytes to protect liver from I/R injury. Conclusions Our data expand on the importance of IRG1/itaconate in nonimmune cells and identify itaconate as a potential therapeutic strategy for this unfavorable postsurgical complication.
- Published
- 2020