上海交通大学医学院Xuemei Tong和Junling Liu共同合作，近期取得重要工作进展。他们研究提出，转酮酶通过限制肌苷诱导的线粒体活性促进MAFLD。相关研究成果2024年3月27日在线发表于《细胞—代谢》杂志上。

据介绍，代谢功能障碍相关脂肪肝（MAFLD）的全球患病率约为25%，且没有批准的治疗方法。

通过代谢组学和蛋白质组学分析，研究人员鉴定了肝转酮症酶（TKT，戊糖磷酸途径的一种代谢酶）在人和小鼠MAFLD中的高表达。高胰岛素血症通过胰岛素受体CCAAT/增强子结合蛋白α轴促进TKT表达。利用肝脏特异性TKT过表达和敲除小鼠模型，研究人员证明TKT对于MAFLD的进展是足够和必要的。

进一步的代谢通量分析显示，Tkt缺失增加了肝肌苷水平，从而激活蛋白激酶A-cAMP反应元件结合蛋白级联，促进磷脂酰胆碱合成，并改善了线粒体功能。

此外，胰岛素诱导肝TKT以限制肌苷依赖性线粒体活性。重要的是，靶向肝TKT的N-乙酰半乳糖胺（GalNAc）-siRNA偶联物对小鼠MAFLD显示出良好的治疗效果。

总之，这一研究揭示了高胰岛素血症调节TKT协调的肌苷代谢和线粒体功能的相关机理，并为MAFLD的预防和治疗提供了一种新的策略。

附：英文原文

Title: Transketolase promotes MAFLD by limiting inosine-induced mitochondrial activity

Author: Lingfeng Tong, Zhangbing Chen, Yangyang Li, Xinxia Wang, Changjie Yang, Yakui Li, Yemin Zhu, Ying Lu, Qi Liu, Nannan Xu, Sijia Shao, Lifang Wu, Ping Zhang, Guangyu Wu, Xiaoyu Wu, Xiaosong Chen, Junwei Fang, Renbing Jia, Tianle Xu, Bin Li, Liang Zheng, Junling Liu, Xuemei Tong

Issue&Volume: 2024-03-27

Abstract: Metabolic dysfunction-associated fatty liver disease (MAFLD) has a global prevalenceof about 25% and no approved therapy. Using metabolomic and proteomic analyses, weidentified high expression of hepatic transketolase (TKT), a metabolic enzyme of thepentose phosphate pathway, in human and mouse MAFLD. Hyperinsulinemia promoted TKTexpression through the insulin receptor-CCAAT/enhancer-binding protein alpha axis.Utilizing liver-specific TKT overexpression and knockout mouse models, we demonstratedthat TKT was sufficient and required for MAFLD progression. Further metabolic fluxanalysis revealed that Tkt deletion increased hepatic inosine levels to activate the protein kinase A-cAMP responseelement binding protein cascade, promote phosphatidylcholine synthesis, and improvemitochondrial function. Moreover, insulin induced hepatic TKT to limit inosine-dependentmitochondrial activity. Importantly, N-acetylgalactosamine (GalNAc)-siRNA conjugatestargeting hepatic TKT showed promising therapeutic effects on mouse MAFLD. Our studyuncovers how hyperinsulinemia regulates TKT-orchestrated inosine metabolism and mitochondrialfunction and provides a novel therapeutic strategy for MAFLD prevention and treatment.

DOI: 10.1016/j.cmet.2024.03.003

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00082-2