Effects and mechanism of Saxagliptin on the atherosclerosis and fatty liver disease in diabetic mice

Abstract:

Objective：To study the effects of saxagliptin，a dipeptidyl peptidase 4（DPP4） inhibitor，on the atherosclerosis and fatty liver disease in the diabetic ApoE-/- mice. Methods：Male diabetic ApoE-/- mice model was established by feeding on a high fat diet and streptozotocin injection，which received the DPP4 inhibitor saxagliptin[15（mg/kg）]（DS，n=8） or saline as a placebo（DM，n=8） once a day by gavage for 12 weeks. Male ApoE-/- mice feeding on a high fat diet as a non-diabetic control group，also divided into saxagliptin treatment group（HS，n=8） and control group（HF，n=8）. Structural changes in the artery and liver，the degree of liver fibrosis and inflammation were evaluated by oil red O and hematoxylin-eosin staining，immunohistochemistry and Western blot. Results：In the diabetic group，saxagliptin intervention significantly reduced the levels of free fat acid（FFA），triglyceride（TG），alanine aminotransferase（ALT），aspartate transaminase（AST） in plasma，also have the same trend of the liver index and IL-1β，NLRP3 protein in the liver（P<0.01） and blood glucose. Lipid droplets in the hepatocytes，liver fibrosis and inflammation were significantly improved（P<0.01） in the group. As contrary，there was no significant changes in plaque area. Conclusion：Saxagliptin has a liver protective effect on diabetic mice，the mechanism may caused by effectively lowering blood glucose and the levels of FFA，TG in plasma，inhibiting the accumulation of macrophages in the liver and the activation of NLRP3 inflammasome，reducing inflammation of the liver. However，no obvious effect was observed on the atherosclerosis.