PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis

Liangchun Yang; Min Xie; Minghua Yang; Yan Yu; Shan Zhu; Wen Hou; Rui Kang; Michael T. Lotze; Timothy R. Billiar; Haichao Wang; Lizhi Cao; Daolin Tang

doi:10.1038/ncomms5436

PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis

Liangchun Yang, Min Xie, Minghua Yang, Yan Yu, Shan Zhu, Wen Hou, Rui Kang, Michael T. Lotze, Timothy R. Billiar, Haichao Wang, Lizhi Cao^*, Daolin Tang

^*Corresponding author for this work

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Abstract

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.

Original language	English
Article number	4436
Journal	Nature Communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms5436
State	Published - 14 Jul 2014

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title = "PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis",

abstract = "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.",

author = "Liangchun Yang and Min Xie and Minghua Yang and Yan Yu and Shan Zhu and Wen Hou and Rui Kang and Lotze, {Michael T.} and Billiar, {Timothy R.} and Haichao Wang and Lizhi Cao and Daolin Tang",

note = "Funding Information: We thank Christine Heiner (Department of Surgery, University of Pittsburgh) for her critical reading of the manuscript. This work was supported by grants from The National Natural Sciences Foundation of China (31171328 and 81370648 to L.C.; 81270616 to Y.Y.; 81100359 to M.Y.) and a grant from the National Institutes of Health (R01CA160417 to D.T.). H.W. is supported by grants from the National Center of Complementary and Alternative Medicine (R01AT005076) and the National Institute of General Medical Sciences (R01GM063075). T.R.B. is supported by grants from the National Institute of General Medical Sciences (R01GM050441 and P50GM053789). This project used University of Pittsburgh Cancer Institute shared resources that are supported in part by award P30CA047904.",

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AU - Yang, Liangchun

AU - Xie, Min

AU - Yang, Minghua

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AU - Zhu, Shan

AU - Hou, Wen

AU - Kang, Rui

AU - Lotze, Michael T.

AU - Billiar, Timothy R.

AU - Wang, Haichao

AU - Cao, Lizhi

AU - Tang, Daolin

N1 - Funding Information: We thank Christine Heiner (Department of Surgery, University of Pittsburgh) for her critical reading of the manuscript. This work was supported by grants from The National Natural Sciences Foundation of China (31171328 and 81370648 to L.C.; 81270616 to Y.Y.; 81100359 to M.Y.) and a grant from the National Institutes of Health (R01CA160417 to D.T.). H.W. is supported by grants from the National Center of Complementary and Alternative Medicine (R01AT005076) and the National Institute of General Medical Sciences (R01GM063075). T.R.B. is supported by grants from the National Institute of General Medical Sciences (R01GM050441 and P50GM053789). This project used University of Pittsburgh Cancer Institute shared resources that are supported in part by award P30CA047904.

PY - 2014/7/14

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N2 - 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.

AB - 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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PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis

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