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

Abstract

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.

• Authors: 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
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 42 Issue 8 Pg. 1256-1266 (Aug 2021) ISSN: 1745-7254 [Electronic] United States
• PMID: 32939034 (Publication Type: Journal Article)
• Copyright: © 2020. CPS and SIMM.

Chemical References

• Anti-Inflammatory Agents
• Antioxidants
• Lipopolysaccharides
• Melitten
• Galactosamine
• Pkm protein, mouse
• Pyruvate Kinase

Topics

• Animals
• Anti-Inflammatory Agents (metabolism, therapeutic use, toxicity)
• Antioxidants (metabolism, therapeutic use, toxicity)
• Galactosamine
• Glycolysis (drug effects)
• Inflammation (drug therapy, etiology)
• Lipopolysaccharides
• Liver Failure, Acute (chemically induced, complications, drug therapy)
• Male
• Melitten (metabolism, therapeutic use, toxicity)
• Mice
• Mice, Inbred C57BL
• Molecular Docking Simulation
• Protein Binding
• Pyruvate Kinase (metabolism)
• RAW 264.7 Cells