Insulin-induced gene 2 protects against hepatic ischemia–reperfusion injury via metabolic remodeling

作者：Yichao Wu, Changbiao Li, Abid Khan, Kangchen Chen, Renyi Su, Shengjun Xu, Yiyang Sun, Fengqiang Gao, Kai Wang, Xiaodong Wang, Zhengxing Lian, Shuo Wang, Mengyuan Yu, Xin Hu, Fan Yang, Shusen Zheng, Nasha Qiu, Zhikun Liu, Xiao Xu · 发表于：Journal of Translational Medicine · 年份：2023 · DOI：10.1186/s12967-023-04564-y · 被引用次数：9 · 研究领域：Endoplasmic Reticulum Stress and Disease、Organ Transplantation Techniques and Outcomes、Cancer, Hypoxia, and Metabolism

Abstract Background Hepatic ischemia–reperfusion (IR) injury is the primary reason for complications following hepatectomy and liver transplantation (LT). Insulin-induced gene 2 (Insig2) is one of several proteins that anchor the reticulum in the cytoplasm and is essential for metabolism and inflammatory responses. However, its function in IR injury remains ambiguous. Methods Insig2 global knock-out (KO) mice and mice with adeno-associated-virus8 (AAV8)-delivered Insig2 hepatocyte-specific overexpression were subjected to a 70% hepatic IR model. Liver injury was assessed by monitoring hepatic histology, inflammatory responses, and apoptosis. Hypoxia/reoxygenation stimulation (H/R) of primary hepatocytes and hypoxia model induced by cobalt chloride (CoCl 2 ) were used for in vitro experiments. Multi-omics analysis of transcriptomics, proteomics, and metabolomics was used to investigate the molecular mechanisms underlying Insig2. Results Hepatic Insig2 expression was significantly reduced in clinical samples undergoing LT and the mouse IR model. Our findings showed that Insig2 depletion significantly aggravated IR-induced hepatic inflammation, cell death and injury, whereas Insig2 overexpression caused the opposite phenotypes. The results of in vitro H/R experiments were consistent with those in vivo. Mechanistically, multi-omics analysis revealed that Insig2 is associated with increased antioxidant pentose phosphate pathway (PPP) activity. The inhibition of glucose-6-phosphate...