Negative regulation of pro-apoptotic AMPK/JNK pathway by itaconate in mice with fulminant liver injury

作者全名："Fan, Kerui; Chen, Kun; Zan, Xinyan; Zhi, Ying; Zhang, Xue; Zhang, Xinyue; Qiu, Jinghuan; Liu, Gang; Li, Longjiang; Tang, Li; Hu, Kai; Wan, Jingyuan; Gong, Xianqiong; Yang, Yongqiang; Zhang, Li"

作者地址："[Fan, Kerui; Chen, Kun; Zan, Xinyan; Zhi, Ying; Zhang, Xue; Zhang, Xinyue; Li, Longjiang; Tang, Li; Yang, Yongqiang; Zhang, Li] Chongqing Med Univ, Basic Med Coll, Dept Pathophysiol, Chongqing, Peoples R China; [Fan, Kerui; Hu, Kai] Chongqing Med Univ, Lab Stem Cell & Tissue Engn, Chongqing, Peoples R China; [Qiu, Jinghuan; Liu, Gang] Chongqing Med Univ, Univ Town Hosp, Dept Emergency, Chongqing 401331, Peoples R China; [Wan, Jingyuan] Chongqing Med Univ, Dept Pharmacol, Chongqing, Peoples R China; [Gong, Xianqiong] Xiamen Hosp Tradit Chinese Med, Hepatol Ctr, Xiamen, Fujian, Peoples R China"

通信作者："Yang, YQ; Zhang, L (通讯作者)，Chongqing Med Univ, Basic Med Coll, Dept Pathophysiol, Chongqing, Peoples R China."

来源：CELL DEATH & DISEASE

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001040994200002

JCR分区：Q1

影响因子：8.1

年份：2023

卷号：14

期号：7

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："Accumulating evidence indicates that metabolic responses are deeply integrated into signal transduction, which provides novel opportunities for the metabolic control of various disorders. Recent studies suggest that itaconate, a highly concerned bioactive metabolite catalyzed by immune responsive gene 1 (IRG1), is profoundly involved in the regulation of apoptosis, but the underlying mechanisms have not been fully understood. In the present study, the molecular mechanisms responsible for the apoptosis-modulatory activities of IRG1/itaconate have been investigated in mice with lipopolysaccharide (LPS)/D-galactosamine (D-Gal)-induced apoptotic liver injury. The results indicated that LPS/D-Gal exposure upregulated the level of IRG1 and itaconate. Deletion of IRG1 resulted in exacerbated hepatocytes apoptosis and liver injury. The phospho-antibody microarray analysis and immunoblot analysis indicated that IRG1 deletion enhanced the activation of AMP-activated protein kinase (AMPK)/c-jun-N-terminal kinase (JNK) pathway in LPS/D-Gal exposed mice. Mechanistically, IRG1 deficiency impaired the anti-oxidative nuclear factor erythroid-2 related factor 2 (Nrf2) signaling and then enhanced the activation of the redox-sensitive AMPK/JNK pathway that promotes hepatocytes apoptosis. Importantly, post-insult supplementation with 4-octyl itaconate (4-OI), a cell-permeable derivate of itaconate, resulted in beneficial outcomes in fulminant liver injury. Therefore, IRG1/itaconate might function as a negative regulator that controls AMPK-induced hepatocyte apoptosis in LPS/D-Gal-induced fulminant liver injury."

基金机构：National Natural Science Foundation of China [81871606]

基金资助正文：AcknowledgementsThis work was supported by grants from the National Natural Science Foundation of China (No. 81871606).