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

Xue Zhang, Ying Zhi, Xinyan Zan, Kerui Fan, Kun Chen, Shuang Zhao, Xinyi Dai, Longjiang Li, Yongqiang Yang, Kai Hu, Xianqiong Gong, Li Zhang

Biochimica et biophysica acta. Molecular basis of disease 2023 Apr

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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 down-regulated 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. Copyright © 2023. Published by Elsevier B.V.

Citation

Xue Zhang, Ying Zhi, Xinyan Zan, Kerui Fan, Kun Chen, Shuang Zhao, Xinyi Dai, Longjiang Li, Yongqiang Yang, Kai Hu, Xianqiong Gong, Li Zhang. Immune response gene 1 deficiency aggravates high fat diet-induced nonalcoholic fatty liver disease via promotion of redox-sensitive AKT suppression. Biochimica et biophysica acta. Molecular basis of disease. 2023 Apr;1869(4):166656