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."













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).