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目的探讨抵抗素(Resistin)在非酒精性脂肪肝(Nonalcoholic fatty liver disease,NAFLD)大鼠胰岛素抵抗(Insulinresistance,IR)中的作用。方法采用改良高脂饲料喂养大鼠建立NAFLD IR大鼠模型,以基础饲料喂养的大鼠作为对照组。分别于开始造模后6、8、10周分别采集2组大鼠血清及肝脏组织,测定血清中甘油三酯(TG)、总胆固醇(TC)、丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)、空腹血糖(Fasting plasma glucose,FPG)和空腹胰岛素(Fasting insulin,FINS)含量,并计算胰岛素敏感性指数(Insulin sensitivity index,ISI);HE染色观察肝脏病理学改变;RT-PCR和Western blot检测肝组织中胰岛素受体底物-2(Insulin receptor substrate-2,IRS-2)、抵抗素(Resistin)和核因子(NF-κB)基因的mRNA转录水平和蛋白的表达水平,并进行相关性分析。结果改良高脂饲料喂养的大鼠一般状况发生改变,显示模型复制成功;TG、TC、ALT和AST值的测定及肝组织学检查证实模型组大鼠存在高血脂和肝功损害,且有IR的现象存在;与对照组比较,模型组Resistin和NF-κB的mRNA转录水平和蛋白表达水平均明显增高,且呈时间依赖性(P<0.05),Resistin与NF-κB的表达呈正相关;IRS-2的mRNA转录水平和蛋白表达水平逐渐下降,且呈时间依赖性(P<0.05),与Resistin的表达呈负相关。结论 NAFLD中IR的发生可能与胰岛素信号通路有关,涉及其始动因素IRS-2的减少和Resistin的增加。Resistin不仅能抑制IRS的磷酸化而影响胰岛素上游信号的正常传导,还可能通过激活NF-κB抑制其下游通路的传导,而加重IR反应。
Objective To investigate the role of Resistin in Insulin resistance (IR) in rats with nonalcoholic fatty liver disease (NAFLD). Methods Rats with NAFLD were fed with modified high-fat diet to establish the model of NAFLD IR rats. The rats fed with basal diet were used as the control group. The serum and liver tissues of two groups were collected at 6, 8, and 10 weeks after the beginning of model establishment respectively. The levels of triglyceride (TG), total cholesterol (TC), alanine aminotransferase (ALT) (AST), fasting plasma glucose (FPG) and fasting insulin (FINS) were measured and the insulin sensitivity index (ISI) was calculated. HE staining was used to observe the changes of liver pathology The mRNA transcription level of Insulin receptor substrate-2 (IRS-2), Resistin and NF-κB in liver tissues were detected by RT-PCR and Western blot, Protein expression level, and correlation analysis. Results The rats fed with high-fat diets changed their general status and showed successful replication of the model. The levels of TG, TC, ALT and AST, and liver histological examination confirmed the presence of hyperlipidemia and liver damage in model rats and IR (P <0.05). The expression of Resistin and NF-κB was positively correlated with the expression of Resistin and NF-κB in the model group. The expression of IRS -2 mRNA and protein expression gradually decreased, and the time-dependent (P <0.05), and the expression of Resistin was negatively correlated. Conclusion The occurrence of IR in NAFLD may be related to the insulin signaling pathway, involving the reduction of IRS-2 and Resistin. Resistin can not only inhibit IRS phosphorylation and affect the normal insulin signal transduction, but also may activate NF-κB inhibition of the downstream pathway conduction, and aggravate the IR response.