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

Ni Fan, Xiuying Zhang, Wei Zhao, Jia Zhao, Dan Luo, Yilu Sun, Ding Li, Chenliang Zhao, Yu Wang, Hongjie Zhang, Jianhui Rong*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

17 Citations (Scopus)

Abstract

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 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.

Original languageEnglish
Pages (from-to)5260-5275
Number of pages16
JournalInternational Journal of Biological Sciences
Volume18
Issue number14
DOIs
Publication statusPublished - Aug 2022

Scopus Subject Areas

  • Ecology, Evolution, Behavior and Systematics
  • Applied Microbiology and Biotechnology
  • Molecular Biology
  • Developmental Biology
  • Cell Biology

User-Defined Keywords

  • macrophage polarization
  • pyruvate kinase M2
  • celastrol
  • covalent modification
  • non-alcoholic fatty liver disease

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