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

Warburg 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 p...

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Autores principales: Fan, Ni, Zhang, Xiuying, Zhao, Wei, Zhao, Jia, Luo, Dan, Sun, Yilu, Li, Ding, Zhao, Chenliang, Wang, Yu, Zhang, Hongjie, Rong, Jianhui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9461663/
https://www.ncbi.nlm.nih.gov/pubmed/36147457
http://dx.doi.org/10.7150/ijbs.73890
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author Fan, Ni
Zhang, Xiuying
Zhao, Wei
Zhao, Jia
Luo, Dan
Sun, Yilu
Li, Ding
Zhao, Chenliang
Wang, Yu
Zhang, Hongjie
Rong, Jianhui
author_facet Fan, Ni
Zhang, Xiuying
Zhao, Wei
Zhao, Jia
Luo, Dan
Sun, Yilu
Li, Ding
Zhao, Chenliang
Wang, Yu
Zhang, Hongjie
Rong, Jianhui
author_sort Fan, Ni
collection PubMed
description Warburg 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 Cys(31) 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.
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spelling pubmed-94616632022-09-21 Covalent Inhibition of Pyruvate Kinase M2 Reprograms Metabolic and Inflammatory Pathways in Hepatic Macrophages against Non-alcoholic Fatty Liver Disease Fan, Ni Zhang, Xiuying Zhao, Wei Zhao, Jia Luo, Dan Sun, Yilu Li, Ding Zhao, Chenliang Wang, Yu Zhang, Hongjie Rong, Jianhui Int J Biol Sci Research Paper Warburg 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 Cys(31) 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. Ivyspring International Publisher 2022-08-15 /pmc/articles/PMC9461663/ /pubmed/36147457 http://dx.doi.org/10.7150/ijbs.73890 Text en © The author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Fan, Ni
Zhang, Xiuying
Zhao, Wei
Zhao, Jia
Luo, Dan
Sun, Yilu
Li, Ding
Zhao, Chenliang
Wang, Yu
Zhang, Hongjie
Rong, Jianhui
Covalent Inhibition of Pyruvate Kinase M2 Reprograms Metabolic and Inflammatory Pathways in Hepatic Macrophages against Non-alcoholic Fatty Liver Disease
title Covalent Inhibition of Pyruvate Kinase M2 Reprograms Metabolic and Inflammatory Pathways in Hepatic Macrophages against Non-alcoholic Fatty Liver Disease
title_full Covalent Inhibition of Pyruvate Kinase M2 Reprograms Metabolic and Inflammatory Pathways in Hepatic Macrophages against Non-alcoholic Fatty Liver Disease
title_fullStr Covalent Inhibition of Pyruvate Kinase M2 Reprograms Metabolic and Inflammatory Pathways in Hepatic Macrophages against Non-alcoholic Fatty Liver Disease
title_full_unstemmed Covalent Inhibition of Pyruvate Kinase M2 Reprograms Metabolic and Inflammatory Pathways in Hepatic Macrophages against Non-alcoholic Fatty Liver Disease
title_short Covalent Inhibition of Pyruvate Kinase M2 Reprograms Metabolic and Inflammatory Pathways in Hepatic Macrophages against Non-alcoholic Fatty Liver Disease
title_sort covalent inhibition of pyruvate kinase m2 reprograms metabolic and inflammatory pathways in hepatic macrophages against non-alcoholic fatty liver disease
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9461663/
https://www.ncbi.nlm.nih.gov/pubmed/36147457
http://dx.doi.org/10.7150/ijbs.73890
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