未折叠蛋白反应-蛋白激酶R样内质网激酶通路对氧化应激诱导生长抑制因子1的影响  

Effect of unfolded protein response-protein kinase R-like endoplasmic reticulum kinase pathway on oxidative stress-induced growth inhibitor 1

作　　者：蔡楠[1] 许雯[1] 刘佳[1] 曾文[1] 林硕[1] 曾龙驿[1] Cai Nan;Xu Wen;Liu Jia;Zeng Wen;Lin Shuo;Zeng Longyi(Department of Endocrinology and Metabolism,Guangdong Provincial Key Laboratory of Diabetology,Third Affiliated Hospital of Sun Yat-sen University,Guangzhou 510630,China)

机构地区：[1]中山大学附属第三医院内分泌与代谢病病科、广东省糖尿病防治重点实验室,广州510630

出　　处：《中华糖尿病杂志》2023年第5期436-444,共9页CHINESE JOURNAL OF DIABETES MELLITUS

基　　金：广东省自然科学基金项目(2022A1515012364,2018B030311012);广州市科技计划项目(202102010175)。

摘　　要：目的寻找肝脏内质网应激过程中未折叠蛋白反应-蛋白激酶R样内质网激酶(UPR-PERK)通路潜在的作用靶点,并在肝脏内质网应激模型中验证UPR-PERK通路对氧化应激诱导生长抑制因子1(Osgin1)是否存在调控关系。方法以GEO数据库作为分析数据的来源,通过GEO2R软件挑选出符合标准的差异基因,对禁食-再喂食、运动及年龄3种生理因素引起显著变化的差异基因使用韦恩图取交集,确定Osgin1是变化显著的基因。通过GENEMANIA数据库验证UPR-PERK通路与Osgin1是否存在直接作用。随后分别在GEO数据库和TCGA数据库中通过3种不同的肝脏内质网应激模型(急性内质网应激模型、非酒精性脂肪性肝病模型及肝癌模型)进一步验证UPR-PERK通路对于Osgin1的调控关系。数据统计采用GraphPadPrism 9.0.0软件,采用Pearson相关分析法分析UPR-PERK通路基因与Osgin1转录水平的相关性。结果与对照组相比,在禁食-再喂食、增加运动及增龄3种生理因素下,Osgin1转录水平分别上调了700%、下调156%以及229%(P<0.05)。经GENEMANIA数据库验证UPR-PERK通路与Osgin1存在直接作用。在内质网应激诱导剂导致的急性肝脏内质网应激模型中,与对照组相比,抑制UPR-PERK通路相关基因(Eif2ak3)可以显著逆转由内质网应激诱导剂Tunicamycin导致的Osgin1 mRNA水平的上调(Osgin1 mRNA下调87%,P<0.001);在非酒精性脂肪性肝病模型中,与对照组相比,通过给予药物实现缓解UPR-PERK通路的同时,Osgin1转录水平也随之下调(减重药物BI4556906组Osgin1 mRNA下调48.0%;EX10970组Osgin1 mRNA下调43.3%;肌醇需要酶1α激动剂IXA4组Osgin1 mRNA下调56.6%;P<0.05);在肝癌模型中,与对照组相比,UPR-PERK通路相关基因与Osgin1转录水平在肝癌组织中显著上调(Osgin1 mRNA上调109%,P<0.001)。结论在生理条件及肝脏内质网应激模型中,UPR-PERK通路的激活上调Osgin1转录水平。Objective To explore the potential target of unfolded protein response-protein kinase R-like endoplasmic reticulum kinase(UPR-PERK)pathway in the process of ER stress in liver,we also tested whether the UPR-PERK pathway could regulate the oxidative stress-induced growth inhibitor 1(Osgin1)in the liver endoplasmic reticulum(ER)stress models.Methods Using GEO database as the source of analysis data,the differentially expressed genes were selected by GEO2R software,using Venn diagram,we identified Osgin1 as the gene with significant variation in the three physiological factors of fasting-refeeding,exercise,and age.The direct interaction between the UPR-PERK pathway and Osgin1 was verified using the GENEMANIA database.Subsequently,we used three different liver endoplasmic reticulum stress models(acute endoplasmic reticulum stress model,non-alcoholic fatty liver disease model and liver cancer model)in GEO Database and TCGA database to further verify the regulatory relationship of UPR-PERK pathway to Osgin1.GraphPadPrism 9.0.0 software was used for statistical analysis.Pearson correlation analysis was used to analyze the correlation between the transcriptional levels of UPR-PERK pathway genes and Osgin1.Results Compared with the control group,fasting-refeeding,increased exercise and aging significantly changed the transcription level of Osgin1(Osgin1 mRNA was up-regulated by 700%,down-regulated by 156%and 229%,respectively,P<0.05).The GENEMANIA database verified the direct interaction between the UPR-PERK pathway and Osgin1.In the model of endoplasmic reticulum(ER)stress,compared with control group,inhibition of UPR-PERK pathway related gene(Eif2ak3)could significantly reverse the up-regulation of Osgin1 mRNA induced by Tunicamycin(Osgin1 mRNA was downregulated by 87%,P<0.001).In the non-alcohol fatty liver model,compared with control group,when the UPR-PERK pathway was alleviated by the administration of drugs,the Osgin1 transcription level was also down-regulated by 48%,43.3%and 56.6%with BI4556906,EX10970 and IXA4 i

关 键 词：未折叠蛋白反应-蛋白激酶R样内质网激酶通路 内质网应激 氧化应激诱导生长抑制因子1 

分 类 号：R346[医药卫生—基础医学]