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

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

Redox biology (2020-08-31)
Fang Xu, Mengmeng Guo, Wei Huang, Lili Feng, Jiazhen Zhu, Kangkang Luo, Jian Gao, Bingfeng Zheng, Ling-Dong Kong, Tao Pang, Xudong Wu, Qiang Xu
초록

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.

MATERIALS
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Sigma-Aldrich
Collagenase from Clostridium histolyticum, 0.2 μm filtered, suitable for release of physiologically active rat hepatocytes, Type IV-S, 0.5-5.0 FALGPA units/mg solid, ≥125 CDU/mg solid
Sigma-Aldrich
Lipopolysaccharides from Escherichia coli O111:B4, purified by phenol extraction
Sigma-Aldrich
Suberic acid bis(N-hydroxysuccinimide ester), ≥95%, powder
Sigma-Aldrich
Mouse KC / CXCL1 ELISA Kit, for serum, plasma and cell culture supernatant