Immune response gene 1 deficiency aggravates high fat diet-induced nonalcoholic fatty liver disease via promotion of redox-sensitive AKT suppression

作者全名："Zhang, Xue; Zhi, Ying; Zan, Xinyan; Fan, Kerui; Chen, Kun; Zhao, Shuang; Dai, Xinyi; Li, Longjiang; Yang, Yongqiang; Hu, Kai; Gong, Xianqiong; Zhang, Li"

作者地址："[Zhang, Xue; Zhi, Ying; Zan, Xinyan; Fan, Kerui; Chen, Kun; Zhao, Shuang; Dai, Xinyi; Li, Longjiang; Yang, Yongqiang; Zhang, Li] Chongqing Med Univ, Basic Med Coll, Dept Pathophysiol, Chongqing, Peoples R China; [Zhang, Xue; Hu, Kai] Chongqing Med Univ, Lab Stem Cell & Tissue Engn, Chongqing, Peoples R China; [Gong, Xianqiong] Xiamen Hosp Tradit Chinese Med, Hepatol Ctr, Xiamen, Fujian, Peoples R China; [Gong, Xianqiong] Xiamen Hosp Tradit Chinese Med, Hepatol Ctr, 1739 Xianyue Rd, Xiamen 361009, Fujian, Peoples R China; [Zhang, Li] Chongqing Med Univ, Basic Med Coll, Dept Pathophysiol, 1 Yixueyuan Rd, Chongqing 400016, Peoples R China"

通信作者："Gong, XQ (通讯作者)，Xiamen Hosp Tradit Chinese Med, Hepatol Ctr, 1739 Xianyue Rd, Xiamen 361009, Fujian, Peoples R China.; Zhang, L (通讯作者)，Chongqing Med Univ, Basic Med Coll, Dept Pathophysiol, 1 Yixueyuan Rd, Chongqing 400016, Peoples R China."

来源：BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000997035800001

JCR分区：Q1

影响因子：4.2

年份：2023

卷号：1869

期号：4

开始页：　

结束页：　

文献类型：Article

关键词：Immune responsive gene 1; Itaconate; Nonalcoholic fatty liver disease; AKT; NRF2

摘要："Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder worldwide. Immune response gene 1 (IRG1) catalyzes the production of bio-active itaconate, which is actively involved in the regulation of signal transduction. A recent study has found that the expression of IRG1 was significantly downregulated in obesity-associated fatty liver, but the potential roles of IRG1 in the development NAFLD remain unclear. The present study found that genetic deletion of IRG1 aggravated high fat diet (HFD)-induced metabolic disturbance, including obesity, dyslipidemia and insulin resistance. In addition, HFD induced more severe liver steatosis and higher serum ALT and AST level in IRG1 KO mice, which were accompanied with altered expression of genes involved in lipid uptake, synthesis and catabolism. RNA-seq and immunoblot analysis indicated that deficiency of IRG1 is associated with suppressed activation of AKT, a master metabolic regulator. Mechanistically, IRG1/itaconate enhanced the antioxidative NRF2 pathway and prevented redox-sensitive suppression of AKT. Interestingly, supplementation with 4-octyl itaconate (4-OI), a cell-permeable derivate of itaconate, alleviated HFD-induced oxidative stress, AKT suppression and liver steatosis. Therefore, IRG1 probably functions as a protective regulator in the development of NAFLD and the cell-permeable 4-OI might have potential value for the pharmacological intervention of NAFLD."

基金机构：National Natural Science Foundation of China [81871606]; Fujian provincial health technology project [2022GGB020]

基金资助正文：This work was supported by the grant from the National Natural Science Foundation of China (No. 81871606) and the grant from Fujian provincial health technology project (2022GGB020) .