Exendin-4通过激活Nrf2/HO-1通路减轻糖尿病小鼠的肝脏氧化应激及纤维化  

Exendin?4 alleviates oxidative stress and liver fibrosis by activating Nrf2/HO?1 in streptozotocin-induced diabetic mice

作　　者：方舒 蔡迎迎[1] 李萍 吴春艳[1] 邹少洲 张雨丹 林晓纯 关美萍[1] FANG Shu;CAI Yingying;LI Ping;WU Chunyan;ZOU Shaozhou;ZHANG Yudan;LIN Xiaochun;GUAN Meiping(Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China)

机构地区：[1]南方医科大学南方医院内分泌代谢科,广东广州510515

出　　处：《南方医科大学学报》2019年第4期464-470,共7页Journal of Southern Medical University

基　　金：国家自然科学基金(81870612;31400992;81470047;81628004)~~

摘　　要：目的探讨Exendin-4对链脲佐菌素(STZ)诱导的糖尿病小鼠肝脏脂质代谢、氧化应激以及纤维化的作用以及其潜在的机制。方法将C57BL/6J小鼠随机分为对照组和糖尿病组(DM)。糖尿病组小鼠给予高脂饮食4周联合STZ造模,对照组小鼠普通饮食。DM小鼠造模成功后,再随机分为糖尿病对照组(DM-con)和糖尿病干预组(DM+E4)。DM+E4组小鼠给予Exendin-4每天1 nmol/kg体重,腹腔注射1次,共8周。监测体重、随机血糖,分析各组小鼠血脂水平,RT-PCR检测肝脏脂质代谢、纤维化和氧化应激指标,HE、天狼猩红以及油红O染色观察肝脏结构变化,Western blot检测肝脏TGF-β1、Nrf2以及HO-1的表达。结果DM组小鼠的血糖和体重较对照组明显升高(P<0.001),肝脏脂质沉积、纤维化以及氧化应激较对照组也显著增加,给予Exendin-4干预未显著改善肝脏的脂质沉积,但是Exendin-4治疗后糖尿病组小鼠血糖及TG明显降低(P<0.05),肝脏纤维化指标TGF-β、α-SMA及Col-I显著降低(P<0.05),抗氧化指标Nrf2、HO-1及GPX4显著升高(P<0.01)同时Nrf2和HO-1的蛋白表达水平也显著升高(P<0.01)。结论 Exendin-4在肝脏脂质沉积未明显减轻的情况下通过激活Nrf2/HO-1信号通路显著改善糖尿病小鼠的肝脏纤维化及氧化应激。Objective To investigate the effects of exendin-4 on hepatic lipid metabolism, fibrosis and oxidative stress in mice with streptozotocin(STZ)-induced diabetes and explore the underlying mechanisms. Methods C57 BL/6 J mice were fed with high-fat diet(HFD) for 4 weeks and received intraperitoneal injections of 120 mg/kg STZ to induce diabetes. After successful modeling, the mice were randomized into diabetic control group and exendin-4 treatment group(DM + E4), and in the latter group, the mice were given a daily dose of 1 nmol/kg of exendin-4 for 8 weeks. The changes in the body weight(BW) and random blood glucose(RBG) in the mice were recorded. The mRNA expressions of the genes related with liver lipid metabolism, fibrosis and oxidative stress were analyzed using RT-PCR, and the structural changes of the liver tissues were observed with HE, Sirius red and oil red O staining;the expressions of TGF-β1, Nrf2 and HO-1 proteins in the liver tissues were detected using Western blotting. Results The diabetic mice showed significantly higher RBG levels and BW with obvious lipid deposition, fibrosis and oxidative stress in the liver as compared with the normal control mice(P<0.001). Exendin-4 treatment of the diabetic mice did not significantly lessened liver lipid deposition but obviously reduced the levels of RBG and TG(P<0.05), lowered the expression levels of liver fibrosis-related genes TGF-β,α-SMA and Col-I(P<0.05), increased the expression levels of the antioxidant genes Nrf2, HO-1 and GPX4(P<0.01), and enhanced the protein expressions of Nrf2 and HO-1 in the liver tissues(P<0.01). Conclusion Exendin-4 improves liver fibrosis and oxidative stress in diabetic mice by activating Nrf2/HO-1 pathway without significantly reducing liver lipid deposition.

关 键 词：EXENDIN-4 糖尿病 肝脏 纤维化 氧化应激 Nrf2/HO-1 

分 类 号：R587.2[医药卫生—内分泌] R575.2[医药卫生—内科学]