沙格列汀对糖尿病小鼠动脉粥样硬化和脂肪性肝炎的影响

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

摘要:

目的：探讨二肽基肽酶4（dipeptidyl peptidase 4，DPP4）抑制剂沙格列汀对2型糖尿病（type 2 diabetes mellitus，T2DM）小鼠合并动脉粥样硬化和脂肪性肝病的影响及其机制。方法：ApoE-/-小鼠高脂喂养、高脂喂养+小剂量链脲佐菌素分别构建非糖尿病、T2DM合并动脉粥样硬化和脂肪性肝病小鼠模型，分为非糖尿病治疗组（HS，n=8）、对照组（HF，n=8），糖尿病治疗组（DS，n=8）、对照组（DM，n=8）。HS、DS组予以沙格列汀15 mg/（kg·d）灌胃治疗，对照组等量生理盐水灌胃，12周后观察主动脉斑块、肝脏脂肪沉积、炎症浸润、纤维化程度以及炎症小体NLRP3活化和炎症介质IL-1β表达变化。结果：DS组较DM组血浆血糖、游离脂肪酸、甘油三酯和ALT、AST水平明显降低（P＜0.01），肝重比明显减小（P＜0.01），肝脏脂肪沉积、巨噬细胞浸润及纤维化程度显著减轻（P＜0.01），肝组织内NLRP3炎症小体及IL-1β表达明显减少（P＜0.01），HS组较HF组上述部分指标也出现明显降低，但HS、DS组较对照组动脉粥样硬化斑块均无明显变化。结论：沙格列汀通过降低血浆血糖和FFA水平，抑制肝脏巨噬细胞聚集、减少NLRP3炎症小体活化等作用抑制糖尿病性脂肪肝的发生和发展，但对动脉粥样硬化没有治疗作用。

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.