转酮醇酶通过限制肌苷诱导的线粒体活性来促进 MAFLD。

Cell metabolism Pub Date : 2024-05-07 Epub Date: 2024-03-27 DOI:10.1016/j.cmet.2024.03.003
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
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摘要

代谢功能障碍相关性脂肪肝(MAFLD)在全球的发病率约为 25%,目前还没有获得批准的治疗方法。通过代谢组学和蛋白质组学分析,我们发现肝脏转酮醇酶 (TKT) 在人类和小鼠 MAFLD 中的高表达,TKT 是磷酸戊糖途径的一种代谢酶。高胰岛素血症通过胰岛素受体-CCAAT/增强子结合蛋白α轴促进了TKT的表达。利用肝脏特异性 TKT 过表达和基因敲除小鼠模型,我们证明了 TKT 是 MAFLD 进展所必需的。进一步的代谢通量分析表明,Tkt缺失会增加肝脏肌苷水平,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,改善线粒体功能。此外,胰岛素还能诱导肝脏 TKT,限制依赖于肌苷的线粒体活性。重要的是,以肝脏TKT为靶点的N-乙酰半乳糖胺(GalNAc)-siRNA共轭物对小鼠MAFLD具有良好的治疗效果。我们的研究揭示了高胰岛素血症是如何调节 TKT 协调的肌苷代谢和线粒体功能的,并为预防和治疗 MAFLD 提供了一种新的治疗策略。
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Transketolase promotes MAFLD by limiting inosine-induced mitochondrial activity.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has a global prevalence of about 25% and no approved therapy. Using metabolomic and proteomic analyses, we identified high expression of hepatic transketolase (TKT), a metabolic enzyme of the pentose phosphate pathway, in human and mouse MAFLD. Hyperinsulinemia promoted TKT expression through the insulin receptor-CCAAT/enhancer-binding protein alpha axis. Utilizing liver-specific TKT overexpression and knockout mouse models, we demonstrated that TKT was sufficient and required for MAFLD progression. Further metabolic flux analysis revealed that Tkt deletion increased hepatic inosine levels to activate the protein kinase A-cAMP response element binding protein cascade, promote phosphatidylcholine synthesis, and improve mitochondrial function. Moreover, insulin induced hepatic TKT to limit inosine-dependent mitochondrial activity. Importantly, N-acetylgalactosamine (GalNAc)-siRNA conjugates targeting hepatic TKT showed promising therapeutic effects on mouse MAFLD. Our study uncovers how hyperinsulinemia regulates TKT-orchestrated inosine metabolism and mitochondrial function and provides a novel therapeutic strategy for MAFLD prevention and treatment.

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