利拉鲁肽极化M2型巨噬细胞改善非酒精性脂肪肝的机制

目的：探讨利拉鲁肽改善2型糖尿病伴随的非酒精性脂肪肝（NAFLD）的作用机制。方法：小鼠随机分为正常组、模型组和利拉鲁肽组3组，每组15只。模型组和利拉鲁肽组采用高糖高脂饲料联合小剂量链脲佐菌素的方法，构建2型糖尿病NAFLD的小鼠模型，利拉鲁肽组皮下注射利拉鲁肽（100 μg/kg），每日1次，连续4周。检测各组小鼠的体质量、肝指数、ALT、AST和TG指标；HE染色及油红O染色观察肝组织病理改变；ELISA法检测血清中IL-4和IL-10的含量；流式细胞术检测M2型巨噬细胞比例；RT-PCR检测IL-4、IL-10、CD206、CD301、MGL-1、MGL-2和Arg-1 mRNA表达。结果：与模型组比，利拉鲁肽组小鼠体质量、肝指数、TG、AST和ALT均明显下降，肝组织中脂肪变性减轻，M2型巨噬细胞比例显著上升（P＜0.001），IL-4、IL-10蛋白表达显著上升（P＜0.05），IL-4、IL-10、CD206、CD301、MGL-1、MGL-2和Arg-1 mRNA表达也显著上升（P＜0.01）。结论：利拉鲁肽对2型糖尿病NAFLD具有保护作用，其机制可能与促进IL-4和IL-10的表达，极化M2型巨噬细胞有关。

Mechanism of liraglutide polarized M2 macrophage in improving nonalcoholic fatty liver disease

Objective: To investigate the potential mechanism of liraglutide in improving nonalcoholic fatty liver disease (NAFLD) associated with type 2 diabetes. Methods: A mouse model of type 2 diabetes with NAFLD was constructed by high-sugar and high-fat diet with a low dose streptozoticin. The mice were randomly divided into 3 groups, normal group, model group and liraglutide group, with 15 mice in each group. The mice in liraglutide group were injected subcutaneously with liraglutide (100 μg/kg) once a day, lasting for 4 weeks. Body weight of each mouse and their liver index, ALT, AST and TG were measured. Pathological changes of liver tissue were observed by HE staining and oil red “O” staining. The levels of interleukin-4 (IL-4) and IL-10 in serum were detected by ELISA. The proportion of M2 macrophages was detected by flow cytometry. The expressions of IL-4, IL-10, CD206, CD301, MGL-1, MGL-2 and arginine-1 mRNA were examined using RT-PCR. Results: Compared with the model group, the body weight, liver index, TG, AST and ALT of the mice in liraglutide group were decreased significantly, the fatty degeneration in the liver tissue was down-regulated, while the proportion of M2 macrophages had an obvious rise (P<0.001), and the expressions of IL-4 and IL-10 were increased notably (P<0.05). Additionally, the expressions of IL-4, IL-10, CD206, CD301, MGL-1, MGL-2 and Arg-1 mRNA were significantly up-regulated in liraglutide group (P<0.01). Conclusion: Liraglutide has protective effect on NAFLD in type 2 diabetes, possibly by promoting the expression of IL-4 and IL-10 to polarize M2 macrophages so that the mechanism of NAFLD get improved.