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Cited by 196Liver Disease Diagnosis and TreatmentLiver physiology and pathologyImmune cells in cancer

Annexin A5 regulates hepatic macrophage polarization via directly targeting PKM2 and ameliorates NASH

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Xu, Fang, Guo, Mengmeng, Huang, Wei, Feng, Lili, Zhu, Jiazhen, Luo, Kangkang, Gao, Jian, Zheng, Bingfeng +4 more·2020·Redox Biology
DOI 10.1016/j.redox.2020.101634PMC PMC7369618
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Abstract

Nonalcoholic steatohepatitis (NASH), the progressive form of nonalcoholic fatty liver disease (NAFLD), is becoming a common chronic liver disease with the characteristics of steatosis, inflammation and fibrosis. Macrophage plays an important role in the development of NASH. In this study, Annexin A5 (Anx A5) is identified with the special effect on hepatic macrophage phenotype shift from M1 to M2. And it is further demonstrated that Anx A5 significantly switches metabolic reprogramming from glycolysis to oxidative phosphorylation in activated macrophages. Mechanistically, the main target of Anx A5 in energy metabolism is confirmed to be pyruvate kinase M2 (PKM2). And we following reveal that Anx A5 directly interacts with PKM2 at ASP101, LEU104 and ARG106, inhibits phosphorylation of Y105, and promotes PKM2 tetramer formation. In addition, based on the results of PKM2 inhibitor (compound 3k) and the phosphorylated mutation (PKM2 (Y105E)), it is proved that Anx A5 exhibits the function in macrophage polarization dependently on PKM2 activity. In vivo studies also show that Anx A5 improves steatosis, inflammation and fibrosis in NASH mice due to specially regulating hepatic macrophages via interaction with PKM2. Therefore, we have revealed a novel function of Anx A5 in hepatic macrophage polarization and HFD-induced NASH, providing important insights into the metabolic reprogramming, which is important for NASH therapy.

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Authors
Xu, F., Guo, M., Huang, W., Feng, L., Zhu, J., Luo, K., Gao, J., Zheng, B., Kong, L.-D., Pang, T., Wu, X., & Xu, Q.
Affiliations
  • Nanjing Drum Tower Hospital (CN)
  • China Pharmaceutical University (CN)
Corresponding author
  • Wu, Xudong
  • Xu, Qiang
ORCID
Venue
Redox Biology
Publisher
Elsevier BV
Published
2020-09
Volume
36
Pages
101634
ISSN
2213-2317 (ISSN-L)
DOI
10.1016/j.redox.2020.101634
PMC
PMC7369618
OpenAlex
W3041869943
Cited by
196
References
8
Citations by year
2026: 33 · 2025: 43 · 2024: 62 · 2023: 25 · 2022: 20 · 2021: 12 · 2020: 1
FWCI
10.40
Type
journal article
Language
en
Open access
Licence
Locations
  • Redox Biology (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • State Key Laboratory of Natural Medicines (SKLNMKF202003)
  • Fundamental Research Funds for the Central Universities (020814380118)
  • National Natural Science Foundation of China (81673487, 81872916, 81730100)
  • National Key New Drug Creation and Manufacturing Program, Ministry of Science and Technology (2018ZX09201002)
  • National Science and Technology Major Project
  • National Key Research and Development Program of China (2017YFA0506000)
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Keywords
annexin V, PKM2, hepatic macrophages, macrophage polarization, nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, metabolic reprogramming, oxidative phosphorylation, glycolysis, hepatic steatosis, liver fibrosis, liver inflammation, high-fat diet
MeSH terms
Animals, Liver, Macrophage Activation, Macrophages, Pyruvate Kinase, Annexin A5, Mice, Non-alcoholic Fatty Liver Disease

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