PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis.
PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis.
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脓毒症中 PKM2 调节 Warburg 效应并促进 HMGB1 释放
DOI：
10.1038/ncomms5436
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发表时间：
2014-07-14
影响因子：
16.6
通讯作者：
Tang, Daolin
中科院分区：
文献类型：
--
作者：
Yang, Liangchun;Xie, Min;Yang, Minghua;Yu, Yan;Zhu, Shan;Hou, Wen;Kang, Rui;Lotze, Michael T.;Billiar, Timothy R.;Wang, Haichao;Cao, Lizhi;Tang, Daolin
越来越多的证据表明代谢重编程在先天性炎症反应的调节中起着重要作用，但其潜在机制仍不清楚。在这里，我们提供的证据支持丙酮酸激酶M2（PKM 2）介导的瓦尔堡效应，即有氧糖酵解，在高迁移率族蛋白1（HMGB 1）的释放调节的新作用。PKM 2与低氧诱导因子1α（HIF 1 α）相互作用，并激活巨噬细胞中有氧糖酵解所必需的HIF-1α依赖性酶的转录。PKM 2、HIF 1 α和糖酵解相关基因的敲低一致地降低乳酸产生和HMGB 1释放。类似地，潜在的PKM 2抑制剂紫草素降低血清乳酸和HMGB 1水平，并保护小鼠免于致死性内毒素血症和脓毒症。总的来说，这些发现揭示了通过调节HMGB 1释放来代谢控制炎症的新机制，并强调了靶向有氧糖酵解在治疗脓毒症和其他炎性疾病中的重要性。
Increasing evidence suggests the important role of metabolic reprogramming in the regulation of the innate inflammatory response, but the underlying mechanism remains unclear. Here, we provide evidence to support a novel role for the pyruvate kinase M2 (PKM2)-mediated Warburg effect, namely aerobic glycolysis, in the regulation of high mobility group box 1 (HMGB1) release. PKM2 interacts with hypoxia-inducible factor 1α (HIF1α) and activates the HIF-1α-dependent transcription of enzymes necessary for aerobic glycolysis in macrophages. Knockdown of PKM2, HIF1α, and glycolysis-related genes uniformly decreases lactate production and HMGB1 release. Similarly, a potential PKM2 inhibitor, shikonin, reduces serum lactate and HMGB1 levels and protects mice from lethal endotoxemia and sepsis. Collectively, these findings shed light on a novel mechanism for metabolic control of inflammation by regulating HMGB1 release and highlight the importance of targeting aerobic glycolysis in the treatment of sepsis and other inflammatory diseases.
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