中文摘要：

目的研究敲除核转录因子NF-E2相关因子2（Nrf2）对高脂饮食诱导小鼠肝脏氧化应激和胰岛素抵抗的影响。方法雄性野生型（WT）和Nrf2基因敲除（Nrf2-/-）ICR小鼠各10只,随机分为WT对照组（control）、Nrf2-/-对照组（KO）、WT高脂饮食组（HFD）、Nrf2-/-高脂饮食组（KOHFD）,每组5只。对照组给予正常饮食,高脂饮食组给予高脂饮食。4周末,行腹腔注射葡萄糖耐量实验（iPGTT）并计算时间-血糖曲线下面积（AUC）。然后处死小鼠,观察肝脏光镜下改变,下腔静脉取血,分光光度法检测空腹血糖、肝脏丙二醛（MDA）及谷胱甘肽（GSH）水平。Western blot检测肝脏JNK、p-JNK、IRS-1及p-IRS-1蛋白水平。结果 HFD和KOHFD组小鼠空腹血糖水平均高于control组和KO组,但是差异无统计学意义（P〉0.05）;iPGTT结果显示,KOHFD组小鼠在15 min时血糖水平和AUC显著高于control组和KO组（P〈0.05）;HFD组和KOHFD组小鼠肝脏MDA较control组和KO组均显著升高（P〈0.05）,GSH均显著降低（P〈0.05）,且KOHFD组和HFD组相比,MDA及GSH均有显著差异（P〈0.05）;Western blot结果显示,各组小鼠肝脏JNK与IRS-1均无明显变化。与control组和KO组相比,KOHFD组小鼠肝脏p-JNK水平显著升高（P〈0.05）、p-IRS-1水平显著降低（P〈0.05）,而HFD组小鼠肝脏p-JNK、p-IRS-1水平与control组比较差异无统计学意义。结论敲除Nrf2可以显著加重高脂饮食诱导的肝脏氧化应激水平,进而促进肝脏胰岛素抵抗的发生。

英文摘要：

Objective To explore the effect of Nrf2 disruption on the development of oxidative stress and intrahepatic insulin resis-tance.Methods Ten male wild type（WT） mice and ten Nrf2-null mice on ICR background were randomly divided into two groups（n=5）,respectively： WT control group,WT high fatty diet（WTHFD） group Nrf2-/-control group,and Nrf2-/-high fatty diet（KOHFD） group.The mice were fed a normal diet and a high fat diet for 4 weeks,respectively.At the end of the experiment,intraperitoneal glucose tolerance test（iPGTT）was performed before sacrifice.Then the levels of blood glucose,hepatic methane dicarboxylic aldehyde（MDA） and glutathione（GSH） were examined.The expression of Jun N-terminal kinase（JNK）,phosphorylated Jun N-terminal kinase（p-JNK）,insulin receptor substrate-1（IRS-1） and phosphorylated insulin receptor substrate（p-IRS-1） were determined by Western blot.The changes of pathology in liver were observed.Results The levels of blood glucose in WTHFD group were higher than those in two control groups,but no significant difference was noted.Compared with two control groups,area under the curve（AUC） in KOHFD group was significantly higher.Moreover,the hepatic MDA concentrations increased in both WTHFD and KOHFD mice at week 4,especially in the KOHFD mice.At week 4,the levels of hepatic GSH decreased significantly in both WTHFD and KOHFD mice,especially in KOHFD mice.Western blot results showed that the expression of JNK and IRS-1 was not significantly different in all groups.However,after feeding HFD for 4 weeks,the protein of p-JNK increased and the protein of p-IRS-1 decreased significantly in KOHFD mice,but no significant difference was observed between WTHFD mice and two control groups.Conclusion Deletion of Nrf2 greatly promotes the onset of HFD-induced intrahepatic insulin resistance in mice due to the aggravated oxidative stress in liver.