Melittin ameliorates inflammation in mouse acute liver failure via inhibition of PKM2-mediated Warburg effect  

作　　者：Xue-gong Fan Si-ya Pei Dan Zhou Peng-cheng Zhou Yan Huang Xing-wang Hu Teng Li Yang Wang Ze-bing Huang Ning Li 

机构地区：[1]Viral hepatitis of Hunan Key Laboratory and Department of Infectious Disease,Xiangya Hospital,Central South University,Changsha 410008,China [2]Institute of Integrative Medicine,Xiangya Hospital,Central South University,Changsha 410008,China [3]Department of Blood Transfusion,Xiangya Hospital,Central South University,Changsha 410008,China

出　　处：《Acta Pharmacologica Sinica》2021年第8期1256-1266,共11页中国药理学报（英文版）

基　　金：supported by the project funded by China Postdoctoral Science Foundation(no's.2016M600639 and 2017T100614);the National Natural Science Foundation of China(no's.81673719,81970550,81700561 and 81873574);Natural Science Foundation of Hunan Province(no's.2019JJ30042 and 11JJ6072)。

摘　　要：Acute liver failure(ALF)is a fatal clinical syndrome with no special drug.Recent evidence shows that modulation of macrophage to inhibit inflammation may be a promising strategy for ALF treatment.In this study we investigated the potential therapeutic effects of melittin,a major peptide component of bee venom both in mice model of ALF and in LPS-stimulated macrophages in vitro,and elucidated the underlying mechanisms.ALF was induced in mice by intraperitoneal injection of D-galactosamine/LPS.Then the mice were treated with melittin(2,4,and 8 mg/kg,ip).We showed that melittin treatment markedly improved mortality,attenuated severe symptoms and signs,and alleviated hepatic inflammation in D-galactosamine/LPS-induced ALF mice with the optimal dose being 4 mg/kg.In addition,melittin within the effective doses did not cause significant in vivo toxicity.In LPS-stimulated RAW264.7 macrophages,melittin(0.7μM)exerted anti-oxidation and anti-inflammation effects.We showed that LPS stimulation promoted aerobic glycolysis of macrophages through increasing glycolytic rate,upregulated the levels of Warburg effect-related enzymes and metabolites including lactate,LDHA,LDH,and GLUT-1,and activated Akt/mTOR/PKM2/HIF-1α signaling.Melittin treatment suppressed M2 isoform of pyruvate kinase(PKM2),thus disrupted the Warburg effect to alleviate inflammation.Molecular docking analysis confirmed that melittin targeted PKM2.In LPS-stimulated RAW264.7 macrophages,knockdown of PKM2 caused similar anti-inflammation effects as melittin did.In D-galactosamine/LPS-induced ALF mice,melittin treatment markedly decreased the expression levels of PKM2 and HIF-1α in liver.This work demonstrates that melittin inhibits macrophage activation-mediated inflammation via inhibition of aerobic glycolysis by targeting PKM2,which highlights a novel strategy of using melittin for ALF treatment.

关 键 词：MELITTIN acute liver failure M2-type pyruvate kinase GLYCOLYSIS Warburg effect INFLAMMATION Akt/mTOR/PKM2/HIF-1αsignaling 

分 类 号：R285.5[医药卫生—中药学]