Yi Z, Deng M, Scott MJ, Fu G, Loughran PA, Lei Z, Li S, Sun P, Yang C, Li W, Xu H, Huang F, Billiar TR. IRG1/Itaconate Activates Nrf2 in Hepatocytes to Protect Against Liver Ischemia-Reperfusion Injury. Hepatology. 2020 Jan 30;10.1002/hep.31147. doi: 10.1002/hep.31147. PMID: 31997373.
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. Here 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 non€hematopoietic 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 (H/R)€induced oxidative stress. Modulation of the IRG1 expression levels in hepatocytes regulated hepatocyte cell death. Importantly, addition of 4€octyl itaconate (4€OI) 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 are the first to 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. Conclusion: Our data expand on the importance of IRG1/itaconate in non€immune cells and identify itaconate as a potential therapeutic strategy for this unfavorable postsurgical complication.
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