Possible contribution of hepatocyte secretion to the elevation of plasma exosomal arginase-1 in high-fat diet-fed mice.

AIMS:The elevation of arginase in vascular tissues decreases nitric oxide production, which is considered as an early step of atherosclerosis in obesity. Previously, we found that arginase-1, one of arginase isozymes, was elevated in the blood plasma of obese adults. The purpose of this study is to elucidate the mechanism by which obesity increases arginase-1 levels in the blood. MAIN METHODS:C57/BL6J male mice fed a high-fat diet (HFD) for 12 weeks were analyzed for factors related to nitric oxide/arginine metabolism and plasma exosomes. To explore the arginase secretory organs, the protein expression levels were analyzed in several organs. To further investigate the relationship between exosomal arginase-1 in plasma, blood glucose levels and arginase-1 in the liver, HepG2 (the human hepatoma cell line) was analyzed after treatment with high glucose. KEY FINDINGS:The increase in arginase activity in the plasma of HFD-fed mice was positively corelated with blood glucose levels and was accompanied by an increase in exosomal arginase-1 levels. Among the organs that highly express arginase, the liver of HFD-fed mice showed a significant increase in arginase-1. The expression of arginase-1 in exosomes and total lysates of HepG2 cells were increased by high glucose exposure. SIGNIFICANCE:Increased exosomal arginase-1 in plasma contributes to increased plasma arginase activity in obesity. The liver is a candidate organ for the secretion of exosomal arginase-1 into plasma, and the p38 pathway induced by high glucose levels may be involved.