Objectives: Immune-responsive gene 1 ( Irg1)-catalyzed production of itaconate is a bioactive metabolite with antibacterial, anti-inflammatory and antioxidant properties. Liver injury is closely related to poor outcomes in septic patients, while prevention of liver injury is essential for the pharmacological control of sepsis. This study investigated the pathological and pharmacological significance of Irg1/itaconate in septic liver injury.Methods: Septic liver injury was induced in mice by injecting lipopolysaccharide (LPS; 15 mg/kg) intraperitoneally. The hepatic mRNA and protein contents of Irg1 were detected. To investigate the pathological meaning of Irg1, septic liver injury was induced in Irg1 knockout mice and their wild-type (WT) littermates, and the degree of liver injury, hepatic inflammation, oxidative stress and the activation of nuclear erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) were subsequently determined. Finally, to explore the gene’s pharmacological potential, 4-octyl itaconate (4-OI; 50 mg/kg), a derivative of itaconate that could cross cell membranes, was administered intraperitoneally. The mobilization of Nrf2/HO-1 and liver injury were then evaluated.Results: The level of Irg1 expression was dramatically enhanced in mice with septic liver injury. Additionally, Irg1 deletion leaded to higher ALT and AST levels, elevated inflammatory and oxidative-stress indicators and compromised stimulation of the Nrf2/HO-1 pathway. However, administering 4-OI restored the Nrf2/HO-1 pathway which mitigated liver injury and inhibited hepatic inflammation and oxidative stress.Conclusions: The results figured that elevation of Irg1 might be a protective event that control the progress of septic liver injury, while 4-OI might have latent significance for the pharmaceutical intervention of septic liver injury.

中文翻译：

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Irg1/衣康酸激活 Nrf2/HO-1 通路并减轻小鼠脓毒性肝损伤

目的：免疫反应基因 1 ( Irg1) 催化产生衣康酸，是一种具有抗菌、抗炎和抗氧化特性的生物活性代谢物。肝损伤与脓毒症患者的不良预后密切相关，而预防肝损伤对于脓毒症的药物控制至关重要。本研究探讨了Irg1/衣康酸在脓毒症性肝损伤中的病理学和药理学意义。方法：通过腹腔注射脂多糖(LPS；15mg/kg)诱导小鼠脓毒症性肝损伤。检测肝脏Irg1 mRNA和蛋白含量。为了探讨Irg1的病理意义，在Irg1敲除小鼠及其野生型（WT）同窝小鼠中诱导脓毒性肝损伤，以及肝损伤程度、肝脏炎症、氧化应激和核红细胞2相关因子2的激活随后测定 (Nrf2)/血红素加氧酶 1 (HO-1)。最后，为了探索该基因的药理学潜力，腹腔注射了衣康酸4-辛酯（4-OI；50 mg/kg），一种可以穿过细胞膜的衣康酸衍生物。然后评估Nrf2/HO-1的动员和肝损伤。结果：脓毒性肝损伤小鼠中Irg1表达水平显着增强。此外，Irg1 缺失会导致 ALT 和 AST 水平升高、炎症和氧化应激指标升高以及 Nrf2/HO-1 通路的刺激受损。然而，给予4-OI可以恢复Nrf2/HO-1通路，从而减轻肝损伤并抑制肝脏炎症和氧化应激。结论：结果表明，Irg1的升高可能是控制脓毒性肝损伤进展的保护性事件，而4-OI可能对脓毒症性肝损伤的药物干预具有潜在意义。