Nrf2对高脂饮食诱导的大鼠胰岛素抵抗的保护作用

Protective effect of Nrf2 on the high fat diet-induced insulin resistance in rats

目的研究姜黄素诱导大鼠肝脏转录因子NF-E2相关因子2(Nrf2)核转位对高脂饮食诱导的大鼠胰岛素抵抗(IR)的保护作用及机制。方法雄性SD大鼠24只随机分为对照组、模型组和干预组,每组8只。对照组给予正常饮食,模型组及干预组均给予髙脂饮食。6周末行胰岛素-正常血糖钳夹术检测各组大鼠IR。之后模型组继续髙脂饮食,干预组予髙脂饮食加姜黄素灌胃200 mg/(kg.d),共4周。第10周末处死所有大鼠观察肝脏病理学变化,检测血清谷草转氨酶(AST)、谷丙转氨酶(ALT),分光光度法检测丙二醛(MDA)、谷胱甘肽(GSH)水平,Western blot检测肝脏Nrf2、胰岛素受体底物-1(IRS-1)、jun N-末端激酶(JNK)、p-JNK及p-IRS-1水平。结果姜黄素干预组大鼠肝脏Nrf2的核转位较其他组明显增加;模型组MDA、AST、ALT较对照组显著升高(P<0.01),干预组MDA、AST、ALT较模型组显著降低(P<0.01);模型组GSH较对照组显著降低(P<0.01),干预组GSH较模型组显著升高(P<0.01)。Western blot结果显示,与模型组比较,干预组Nrf2核转位增加、p-JNK水平降低、p-IRS-1水平增加、JNK及IRS-1水平无明显变化。结论诱导Nrf2核转位能够减轻大鼠肝脏氧化应激损伤,进而改善肝脏的胰岛素抵抗。

Objective To investigate the protective effect of nuclear factor E2-related factor 2（Nrf2） nuclear translocation on the high fat diet induced-insulin resistance in rats and to explore its possible mechanism.Methods Twenty-four male SD rats were randomized into 3 groups：control group（n=8）,model group（n=8） and curcumine-treated group（n=8）.Rats were given normal diet in control group,and high fat diet in the other groups.IR models were validated with hyperinsulinemic-euglycemic clamp test in model group and control group after 6 weeks.Then rats were continuously fed with normal diet in control group,high fat diet in model group,while the rats were additionally fed with oral curcumine at the dose of 200 mg/kg per day for 4 weeks based on high fat diet in curcumine-treated group.At the end of week 10,the levels of AST,ALT,malondialdehyde（MDA） and glutathione（GSH） were measured.The levels of Nrf2,JNK/p-JNK and IRS-1/p-IRS-1 were determined by Western blot,and the pathological changes of liver tissues were observed.Results Curcumine resulted in markedly nuclear translocation of Nrf2.Compared with control group,the levels of MDA,AST and ALT increased significantly in model group（P0.01）.However,the levels of MDA,AST and ALT in curcumine-treated group decreased significantly compared with model group（P0.01）.Compared with control group,the level of GSH decreased significantly in model group（P0.01）.However,the levels of GSH in curcumine-treated group increased significantly compared with model group（P0.01）.Compared with model group,the levels of p-IRS-1 increased and the level of p-JNK decreased in curcumine-treated group,but the levels of IRS-1 and JNK were not significantly different.Conclusion Nuclear translocation of Nrf2 can reduce oxidative stress injury and improve insulin resistance in rats.