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
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膜联蛋白 A5 通过直接靶向 PKM2 调节肝巨噬细胞极化并改善 NASH
DOI：
10.1016/j.redox.2020.101634
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发表时间：
2020-07
期刊：
影响因子：
11.4
通讯作者：
Qiang Xu
中科院分区：
文献类型：
--
作者：
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
非酒精性脂肪性肝炎（Nonalcoholic steatohepatitis，NASH）是非酒精性脂肪性肝病（nonalcoholic fatty liver disease，NAFLD）的进展形式，是一种以脂肪变性、炎症和纤维化为特征的常见慢性肝病。巨噬细胞在NASH的发生发展中起重要作用。在这项研究中，膜联蛋白A5（Anx A5）被确定对肝脏巨噬细胞表型从M1转变为M2具有特殊作用。进一步证明Anx A5在活化的巨噬细胞中显著地将代谢重编程从糖酵解转换为氧化磷酸化。在机制上，Anx A5在能量代谢中的主要靶标被证实是丙酮酸激酶M2（PKM2）。我们随后发现Anx A5在ASP 101、LEU 104和ARG 106处直接与PKM 2相互作用，抑制Y105的磷酸化，并促进PKM 2四聚体的形成。此外，基于PKM2抑制剂（化合物3k）和磷酸化突变（PKM2（Y105E））的结果，证明Anx A5在巨噬细胞极化中表现出依赖于PKM2活性的功能。体内研究还表明，Anx A5通过与PKM2相互作用特异性调节肝巨噬细胞，从而改善NASH小鼠的脂肪变性、炎症和纤维化。因此，我们揭示了Anx A5在肝巨噬细胞极化和HFD诱导的NASH中的新功能，为NASH治疗的代谢重编程提供了重要的见解。
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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作者：
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影响因子：
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影响因子：
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作者：
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