基于JNK信号通路探讨自噬、胰岛素抵抗在非酒精性脂肪性肝病中的发病机制  

Explore the mechanism of autophagy and insulin resistance in non-alcoholic fatty liver disease based on JNK signaling pathway

作　　者：延华[1] 柴春艳 张丹[1] 赵媛[1] 李敏[2] YAN Hua;CHAI Chunyan;ZHANG Dan;ZHAO Yuan;LI Min(Departments of Geriatrics,Shaanxi Provincial People’s Hospital,Xi’an 710068,China)

机构地区：[1]陕西省人民医院老年病院,陕西西安710068 [2]陕西省人民医院保健办,陕西西安710068

出　　处：《陕西医学杂志》2023年第11期1506-1510,共5页Shaanxi Medical Journal

基　　金：陕西省重点研发计划项目(2022SF-450,2021SF-352)。

摘　　要：目的:探讨基于JNK信号通路自噬、胰岛素抵抗在非酒精性脂肪性肝病(NAFLD)中的发病机制。方法:采用高脂饮食喂养SD大鼠建立NAFLD模型,分为正常饮食组(ND组)、高脂饮食组(HFD组)、JNK抑制剂SP600125治疗组(SP600125组)、磷酸盐缓冲盐水PBS对照组(Control组)。ND组喂食正常饲料,HFD组、SP600125组和Control组喂食高脂饲料20周,SP600125组大鼠腹腔注射SP600125、Control组大鼠注射磷酸盐缓冲盐水PBS,每天1次,再延长8周。检测大鼠的胰岛素抵抗、C-Jun N末端激酶(JNK)信号通路及自噬相关蛋白的表达。结果:与ND组大鼠对比HFD组血糖、游离脂肪酸及胰岛素水平升高(均P<0.05),HFD组磷酸化JNK1(p-JNK1)蛋白表达水平显著升高(P<0.05)。自噬相关蛋白Beclin-1(Beclin-1)、自噬相关蛋白LC-3Ⅱ(LC-3Ⅱ)、自噬相关基因3(Atg 3)和自噬相关基因5(Atg 5)表达水平升高(均P<0.05)。HFD组的胰岛素受体(IR)β亚基、IR底物-1和蛋白激酶B的磷酸化(p-IRβ、p-IRS-1和p-Akt)表达水平升高(均P<0.05)。与Control组对比,SP600125组的磷酸化JNK1(p-JNK1)蛋白表达水平显著下降(P<0.01),SP600125降低了自噬相关蛋白LC-3Ⅱ、Beclin-1、Atg 3和Atg 5的表达水平(均P<0.01),以及p-IRβ、p-IRS-1和p-Akt的表达水平(均P<0.01)。SP600125组游离脂肪酸及胰岛素水平下降(均P<0.01)。结论:抑制JNK可抑制自噬、减轻胰岛素抵抗,JNK抑制可能为NAFLD提供一种新的治疗策略。Objective:To explore the mechanism of autophagy and insulin resistance in non-alcoholic fatty liver disease(NAFLD)based on JNK signaling pathway.Methods:SD rats were fed a high-fat diet to establish NAFLD model,which was divided into normal diet group(ND group),high-fat diet group(HFD group),JNK inhibitor SP600125 treatment group(SP600125 group)and phosphate buffered saline PBS Control group(Control group).ND group was fed normal diet,HFD group,SP600125 group and Control group were fed high fat diet for 20 weeks.SP600125 group was intraperitoneally injected with SP600125 and Control group was intraperitoneally injected with phosphate buffered saline(PBS)once a day for another 8 weeks.Insulin resistance,the expressions of c-Jun N-terminal kinase(JNK)signaling pathway and autophagy related proteins were detected.Results:The levels of blood glucose,free fatty acid and insulin in HFD group were higher than those in ND group(all P<0.05).The expression level of phosphorylated JNK1(p-JNK1)protein in HFD group was significantly increased(P<0.05).The expression levels of autophagy associated protein Beclin-1(Beclin-1),autophagy associated protein LC-3Ⅱ(LC-3Ⅱ),autophagy associated gene 3(Atg 3)and Atg 5 were increased(all P<0.05).The expression levels of insulin receptor(IR)beta subunits,IR substrate-1 and protein kinase B phosphorylation(p-IRβ,p-IRS-1 and p-Akt)were increased in HFD group(all P<0.05).Compared with Control group,the expression level of phosphorylated JNK1(p-JNK1)protein was significantly decreased,and the expression levels of autophagy related proteins LC-3Ⅱ,Beclin-1,Atg 3 and Atg 5,and the levels of p-IRβ,p-IRS-1 and p-Akt in SP600125 group were decreased(all P<0.01).The levels of free fatty acids and insulin in SP600125 group were decreased(both P<0.01).Conclusion:Inhibiting JNK can inhibit autophagy and reduce insulin resistance.Therefore,JNK inhibition may provide a new treatment strategy for NAFLD.

关 键 词：JNK信号通路 自噬 胰岛素抵抗 非酒精性脂肪性肝病 SP600125 游离脂肪酸 

分 类 号：R575.5[医药卫生—消化系统]