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Article: Covalent Inhibition of Pyruvate Kinase M2 Reprograms Metabolic and Inflammatory Pathways in Hepatic Macrophages against Non-alcoholic Fatty Liver Disease

TitleCovalent Inhibition of Pyruvate Kinase M2 Reprograms Metabolic and Inflammatory Pathways in Hepatic Macrophages against Non-alcoholic Fatty Liver Disease
Authors
Issue Date2022
Citation
International Journal of Biological Sciences , 2022, v. 18, p. 5260-5275 How to Cite?
AbstractWarburg effect of aerobic glycolysis in hepatic M1 macrophages is a major cause for metabolic dysfunction and inflammatory stress in non-alcoholic fatty liver disease (NAFLD). Plant-derived triterpene celastrol markedly inhibited macrophage M1 polarization and adipocyte hypertrophy in obesity. The present study was designed to identify the celastrol-bound proteins which reprogrammed metabolic and inflammatory pathways in M1 macrophages. Pyruvate kinase M2 (PKM2) was determined to be a major celastrol-bound protein. Peptide mapping revealed that celastrol bound to the residue Cys31 while covalent conjugation altered the spatial conformation and inhibited the enzyme activity of PKM2. Mechanistic studies showed that celastrol reduced the expression of glycolytic enzymes (e.g., GLUT1, HK2, LDHA, PKM2) and related signaling proteins (e.g., Akt, HIF-1α, mTOR), shifted aerobic glycolysis to mitochondrial oxidative phosphorylation and skewed macrophage polarization from inflammatory M1 type to anti-inflammatory M2 type. Animal experiments indicated that celastrol promoted weight loss, reduced serum cholesterol level, lipid accumulation and hepatic fibrosis in the mouse model of NAFLD. Collectively, the present study demonstrated that celastrol might alleviate lipid accumulation, inflammation and fibrosis in the liver via covalent modification of PKM2.
Persistent Identifierhttp://hdl.handle.net/10722/319287
ISSN
2023 Impact Factor: 8.2
2023 SCImago Journal Rankings: 2.114
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorFAN, N-
dc.contributor.authorZHANG, X-
dc.contributor.authorZhao, W-
dc.contributor.authorZhao, J-
dc.contributor.authorLuo, D-
dc.contributor.authorSUN, Y-
dc.contributor.authorLI, D-
dc.contributor.authorZHAO, C-
dc.contributor.authorWang, Y-
dc.contributor.authorZHANG, H-
dc.contributor.authorRong, J-
dc.date.accessioned2022-10-14T05:10:34Z-
dc.date.available2022-10-14T05:10:34Z-
dc.date.issued2022-
dc.identifier.citationInternational Journal of Biological Sciences , 2022, v. 18, p. 5260-5275-
dc.identifier.issn1449-2288-
dc.identifier.urihttp://hdl.handle.net/10722/319287-
dc.description.abstractWarburg effect of aerobic glycolysis in hepatic M1 macrophages is a major cause for metabolic dysfunction and inflammatory stress in non-alcoholic fatty liver disease (NAFLD). Plant-derived triterpene celastrol markedly inhibited macrophage M1 polarization and adipocyte hypertrophy in obesity. The present study was designed to identify the celastrol-bound proteins which reprogrammed metabolic and inflammatory pathways in M1 macrophages. Pyruvate kinase M2 (PKM2) was determined to be a major celastrol-bound protein. Peptide mapping revealed that celastrol bound to the residue Cys31 while covalent conjugation altered the spatial conformation and inhibited the enzyme activity of PKM2. Mechanistic studies showed that celastrol reduced the expression of glycolytic enzymes (e.g., GLUT1, HK2, LDHA, PKM2) and related signaling proteins (e.g., Akt, HIF-1α, mTOR), shifted aerobic glycolysis to mitochondrial oxidative phosphorylation and skewed macrophage polarization from inflammatory M1 type to anti-inflammatory M2 type. Animal experiments indicated that celastrol promoted weight loss, reduced serum cholesterol level, lipid accumulation and hepatic fibrosis in the mouse model of NAFLD. Collectively, the present study demonstrated that celastrol might alleviate lipid accumulation, inflammation and fibrosis in the liver via covalent modification of PKM2.-
dc.languageeng-
dc.relation.ispartofInternational Journal of Biological Sciences-
dc.titleCovalent Inhibition of Pyruvate Kinase M2 Reprograms Metabolic and Inflammatory Pathways in Hepatic Macrophages against Non-alcoholic Fatty Liver Disease-
dc.typeArticle-
dc.identifier.emailZhao, J: zhaojia7@hku.hk-
dc.identifier.emailWang, Y: yuwanghk@hku.hk-
dc.identifier.emailRong, J: jrong@hku.hk-
dc.identifier.authorityWang, Y=rp00239-
dc.identifier.authorityRong, J=rp00515-
dc.identifier.doi10.7150/ijbs.73890-
dc.identifier.scopuseid_2-s2.0-85137318250-
dc.identifier.hkuros338573-
dc.identifier.volume18-
dc.identifier.spage5260-
dc.identifier.epage5275-
dc.identifier.isiWOS:000863294700004-

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