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

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.

Hepatic macrophages: Key players in the development and progression of liver fibrosis

“…Annexin A5 (Anx A5), a member of the annexin family, switches metabolic reprogramming from glycolysis to oxidative phosphorylation in hepatic macrophages via interacting with pyruvate kinase M2 (PKM2). This metabolic reprogramming process stimulates the polarisation of hepatic macrophages and a phenotypic switch from M1 to M2, thereby ameliorating steatosis, inflammation, and liver fibrosis in the HFD NASH model 118 . These findings indicate a dual role of macrophage metabolism in the pathophysiology of liver fibrosis.…”

Annexin Animal Models—From Fundamental Principles to Translational Research

“…Moreover, administration of AnxA5 fused to stromal-derived factor 1, a cytokine that protects the heart from ischaemic injury, accumulated at the myocardium, probably via binding to PS on apoptotic cells, and provided cardioprotection, as judged by attenuated apoptosis, enhanced angiogenesis, reduced infarcted size and improved cardiac function after MI [ 259 ]. Finally, AnxA5 administration improved steatosis, inflammation and fibrosis in nonalcoholic steatohepatitis [ 260 ]. Interestingly, the underlying mechanism in the latter studies might not involve AnxA5 binding to PS, but AnxA5 interacting with pyruvate kinase 2, leading to metabolic reprogramming from glycolysis to oxidative phosphorylation in macrophages [ 260 ] ( Table 5 d).…”

“…Finally, AnxA5 administration improved steatosis, inflammation and fibrosis in nonalcoholic steatohepatitis [ 260 ]. Interestingly, the underlying mechanism in the latter studies might not involve AnxA5 binding to PS, but AnxA5 interacting with pyruvate kinase 2, leading to metabolic reprogramming from glycolysis to oxidative phosphorylation in macrophages [ 260 ] ( Table 5 d).…”

Ceria Nanoparticles Ameliorate Renal Fibrosis by Modulating the Balance Between Oxidative Phosphorylation and Aerobic Glycolysis

“…In the present study, it was demonstrated that CeNP-PEG increase mitochondrial OXPHOS activity as judged by mitochondrial OCR and also decrease glycolytic activity as judged by ECAR. [36,37] Since EMT is accompanied by the increased expression of glycolytic enzymes. In our study, it was demonstrated that the protein levels of HK1 and HK2, which are the critical metabolic kinase of the aerobic glycolysis, significantly decreased after treatment with CeNP-PEG.…”