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Abstract
BackgroundRecent investigations indicate that schistosome infection is closely associated with aberrant glycolipid metabolism. However, the actual glycolipid metabolism gene expression, as well as the possible pathways that regulate glycolipid metabolism in the schistosome-infected liver, has not been extensively explored.MethodsIn this study, we evaluated the dynamic expression of glycolipid metabolism-associated genes and proteins in the livers from mice infected with Schistosoma japonicum at the indicated time points using real-time PCR and immunofluorescence. Then, cultures of macrophages were treated with schistosome soluble egg antigen (SEA) to detect the expression levels of genes associated with glucose and lipid metabolism in order to identify macrophages metabolic characteristics in response to these antigens. Furthermore, SEA-stimulated macrophages were co-cultures with hepatocytes and detected the effects of macrophages on the gene expression of hepatocytes metabolism.ResultsThe expression of glycolysis-related genes (Ldha, Glut4, Pkm2, Glut1, Pfkfb3, Aldoc, HK2, Pfk) in the liver were upregulated but the gluconeogenesis gene (G6pc) was downregulated during S. japonicum infection. In addition, the mRNA levels of fatty acid (FA) oxidation-related genes (Ucp2, Atp5b, Pparg) in the liver were significantly upregulated; however, the FA synthesis genes (Fas, Acc, Scd1, Srebp1c) and lipid uptake gene (Cd36) were downregulated post-S. japonicum-infection. In consistence with these data, stimulation with SEA in vitro significantly enhanced the gene expression that involved in glycolysis and FA oxidation, but decreased genes related to gluconeogenesis, FA synthesis and lipid uptake in macrophages. The levels of phosphorylated AMPK, AKT and mTORC1 were increased in macrophages after SEA stimulation. Inhibition of phosphorylated AMPK, AKT and mTORC1 promoted SEA-treated macrophages to produce glucose. In addition, suppression of phosphorylated-AMPK, but not phosphorylated-AKT and phosphorylated-mTOR, induced the lipid accumulation in SEA-stimulated macrophages. Furthermore, SEA-treated macrophages significantly reduced the expression of Acc mRNA in hepatocytes in vitro.ConclusionsThese findings reveal S. japonicum infection induces dynamic changes in the expression levels of genes involved in catabolism (glucose uptake, glycolysis and fatty acid oxidation) and suppressing anabolism (glycogen synthesis) in the liver, which could occur via macrophages’ metabolic states, particularly those involved in the AMPK, AKT and mTORC1 pathways.
Highlights
Recent investigations indicate that schistosome infection is closely associated with aberrant glycolipid metabolism
Our study systematically investigated the kinetics of the gene expression related to hepatic glycolipid metabolism in experimentally S. japonicum-infected mice and examined the potential effects of schistosomal egg antigens on the macrophage metabolism, which provide a better understanding of the mechanisms by which helminth infection regulates host metabolic homeostasis
Expression profiling of hepatic genes associated with glucose metabolism during Schistosoma japonicum infection Our previous study showed that the whole-body and hepatic insulin sensitivity were decreased in S
Summary
Recent investigations indicate that schistosome infection is closely associated with aberrant glycolipid metabolism. Our previous study indicated that chronic S. japonicum infection or SEA treatment in the mouse model can regulate host metabolic homeostasis through promoting Th2 responses in the liver [5]. The liver, a main metabolic organ of the body, plays major metabolic roles in regulating the homeostasis of glucose and lipids, as well as amino acids during alterations of metabolic conditions [6]. As one of the major cellular constituents and important immune regulators of liver pathology in schistosomiasis [7,8,9], macrophages have been reported to play critical roles in maintaining hepatic informatory and metabolic homeostasis. The M1 macrophages exhibit a high level of arginine metabolism and maintain the glycolytic activity by enhancing the expression of the pro-glycolytic 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3); M2 macrophages shift macrophage metabolism into fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) states, directed by signaling via IL-4 [10]. It is suggested that maintaining the balance of macrophage metabolic homeostasis may be a potential therapeutic strategy for metabolic diseases
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