Int J Biol Sci 2022; 18(14):5260-5275. doi:10.7150/ijbs.73890 This issue Cite

Research Paper

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

Ni Fan1, Xiuying Zhang1, Wei Zhao1, Jia Zhao1, Dan Luo1, Yilu Sun1, Ding Li2, Chenliang Zhao3, Yu Wang4, Hongjie Zhang3, Jianhui Rong1,5✉

1. School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
2. College of Chemistry and Pharmacy, Northwest A&F University, Shaanxi, China.
3. School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.
4. Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
5. The University of Hong Kong Shenzhen Institute of Research and Innovation (HKU-SIRI), Shenzhen, China.

Citation:
Fan N, Zhang X, Zhao W, Zhao J, Luo D, Sun Y, Li D, Zhao C, Wang Y, Zhang H, Rong J. Covalent Inhibition of Pyruvate Kinase M2 Reprograms Metabolic and Inflammatory Pathways in Hepatic Macrophages against Non-alcoholic Fatty Liver Disease. Int J Biol Sci 2022; 18(14):5260-5275. doi:10.7150/ijbs.73890. https://www.ijbs.com/v18p5260.htm
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Abstract

Graphic 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.

Keywords: macrophage polarization, pyruvate kinase M2, celastrol, covalent modification, non-alcoholic fatty liver disease


Citation styles

APA
Fan, N., Zhang, X., Zhao, W., Zhao, J., Luo, D., Sun, Y., Li, D., Zhao, C., Wang, Y., Zhang, H., Rong, J. (2022). Covalent Inhibition of Pyruvate Kinase M2 Reprograms Metabolic and Inflammatory Pathways in Hepatic Macrophages against Non-alcoholic Fatty Liver Disease. International Journal of Biological Sciences, 18(14), 5260-5275. https://doi.org/10.7150/ijbs.73890.

ACS
Fan, N.; Zhang, X.; Zhao, W.; Zhao, J.; Luo, D.; Sun, Y.; Li, D.; Zhao, C.; Wang, Y.; Zhang, H.; Rong, J. Covalent Inhibition of Pyruvate Kinase M2 Reprograms Metabolic and Inflammatory Pathways in Hepatic Macrophages against Non-alcoholic Fatty Liver Disease. Int. J. Biol. Sci. 2022, 18 (14), 5260-5275. DOI: 10.7150/ijbs.73890.

NLM
Fan N, Zhang X, Zhao W, Zhao J, Luo D, Sun Y, Li D, Zhao C, Wang Y, Zhang H, Rong J. Covalent Inhibition of Pyruvate Kinase M2 Reprograms Metabolic and Inflammatory Pathways in Hepatic Macrophages against Non-alcoholic Fatty Liver Disease. Int J Biol Sci 2022; 18(14):5260-5275. doi:10.7150/ijbs.73890. https://www.ijbs.com/v18p5260.htm

CSE
Fan N, Zhang X, Zhao W, Zhao J, Luo D, Sun Y, Li D, Zhao C, Wang Y, Zhang H, Rong J. 2022. Covalent Inhibition of Pyruvate Kinase M2 Reprograms Metabolic and Inflammatory Pathways in Hepatic Macrophages against Non-alcoholic Fatty Liver Disease. Int J Biol Sci. 18(14):5260-5275.

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