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

Xue-gong Fan1, Si-ya Pei1, Dan Zhou2, Peng-cheng Zhou1, Yan Huang1, Xing-wang Hu1, Teng Li2, Yang Wang1,2, Ze-bing Huang1, Ning Li1,3
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
Correspondence to: Ning Li:,
DOI: 10.1038/s41401-020-00516-0
Received: 24 November 2019
Accepted: 19 August 2020
Advance online: 16 September 2020


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 (0.7 μM) 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.
Keywords: melittin; acute liver failure; M2-type pyruvate kinase; glycolysis; Warburg effect; inflammation; Akt/mTOR/PKM2/HIF-1α signaling

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