TY - JOUR
T1 - PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis
AU - Yang, Liangchun
AU - Xie, Min
AU - Yang, Minghua
AU - Yu, Yan
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
Y1 - 2014/7/14
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.
UR - http://www.scopus.com/inward/record.url?scp=84904489275&partnerID=8YFLogxK
U2 - 10.1038/ncomms5436
DO - 10.1038/ncomms5436
M3 - Article
C2 - 25019241
AN - SCOPUS:84904489275
SN - 2041-1723
VL - 5
JO - Nature Communications
JF - Nature Communications
M1 - 4436
ER -