Activation of PKM2 metabolically controls fulminant liver injury via restoration of pyruvate and reactivation of CDK1

作者全名："Lv, Xiaohui; Zhou, Honghong; Hu, Kai; Lin, Ling; Yang, Yongqiang; Li, Longjiang; Tang, Li; Huang, Jiayi; Shen, Yi; Jiang, Rong; Wan, Jingyuan; Zhang, Li"

作者地址："[Lv, Xiaohui; Zhou, Honghong; Lin, Ling; Yang, Yongqiang; Li, Longjiang; Tang, Li; Huang, Jiayi; Shen, Yi; Zhang, Li] Chongqing Med Univ, Dept Pathophysiol, 1 Yixueyuan Rd, Chongqing 400016, Peoples R China; [Lv, Xiaohui; Hu, Kai; Jiang, Rong; Zhang, Li] Chongqing Med Univ, Lab Stem Cell & Tissue Engn, Chongqing, Peoples R China; [Hu, Kai] Chongqing Med Univ, Dept Histol & Embryol, Chongqing, Peoples R China; [Wan, Jingyuan] Chongqing Med Univ, Dept Pharmacol, 1 Yixueyuan Rd, Chongqing 400016, Peoples R China"

通信作者："Zhang, L (corresponding author), Chongqing Med Univ, Dept Pathophysiol, 1 Yixueyuan Rd, Chongqing 400016, Peoples R China.; Wan, JY (corresponding author), Chongqing Med Univ, Dept Pharmacol, 1 Yixueyuan Rd, Chongqing 400016, Peoples R China."

来源：PHARMACOLOGICAL RESEARCH

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:000696677900035

JCR分区：Q1

影响因子：9.3

年份：2021

卷号：172

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Pyruvate kinase M2; Pyruvate; Cyclin dependent kinase 1; Apoptosis; Liver injury

摘要："Accumulating evidence indicates that metabolic events profoundly modulate the progression of various diseases. Pyruvate is a central metabolic intermediate in glucose metabolism. In the present study, the metabolic status of pyruvate and its pharmacological significance has been investigated in mice with lipopolysaccharide/D-galactosamine (LPS/D-Gal)-induced fulminant liver injury. Our results indicated that LPS/D-Gal exposure decreased the activity of pyruvate kinase and the content of pyruvate, which were reversed by the PKM2 activator TEPP-46. Pretreatment with TEPP-46 or supplementation with the cell-permeable pyruvate derivate ethyl pyruvate (EP) attenuated LPS/D-Gal-induced liver damage. Interestingly, post-insult intervention of pyruvate metabolism also resulted in beneficial outcomes. The phospho-antibody microarray analysis and immunoblot analysis found that the inhibitory phosphorylation of cyclin dependent kinase 1 (CDK1) was reversed by TEPP-46, DASA-58 or EP. In addition, the therapeutic benefits of PKM2 activator or EP were blunted by the CDK1 inhibitor Ro 3306. Our data suggests that LPS/D-Gal exposure-induced decline of pyruvate might be a novel metabolic mechanism underlies the development of LPS/D-Gal-induced fulminant liver injury, PKM2 activator or pyruvate derivate might have potential value for the pharmacological intervention of fulminant liver injury."

基金机构：National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81871606]; Science and Technology Research Program of Chongqing Municipal Education Commission [KJQN201900435]

基金资助正文：This work was supported by the grants from the National Natural Science Foundation of China (No. 81871606) and the grant from the Science and Technology Research Program of Chongqing Municipal Education Commission (No. KJQN201900435).