内质网应激在间歇低氧所致肝脏胰岛素抵抗中的作用

The role of endoplasmic reticulum stress in hepatic insulin resistance caused by intermittent hypoxia

目的探讨大鼠内质网应激在间歇低氧所致肝脏胰岛素抵抗中的作用。方法将24只SD大鼠随机分为对照组(NC组)及间歇低氧组(CIH组),NC组置于常氧环境12周,CIH组先予间歇低氧8周、随后恢复常氧饲养至第12周。两组均于基线、第8周、第12周测定空腹血糖(FBG)、空腹胰岛素(FINS)、及肝脏肌醇依赖酶1α(IRE1α)、剪切型X-box结合蛋白1(XBP1s)、叉形头转录因子1(FoxO1)、活化转录因子6(ATF6)、环腺苷酸反应元件结合蛋白(CREB)、CREB调控转录辅激活因子-2(CRTC2)、内质网膜上的I型跨膜激酶(PERK)、真核翻译起始因子2α(eIF2α)、蛋白激酶B(AKT)、磷酸烯醇式丙酮酸羧激酶(PEPCK)、葡萄糖6磷酸酶(G6Pase)mRNA的表达水平。结果两组基线时各观察指标差异无统计学意义;8周时,CIH组FBG、FINS及IRE1α、XBP1s、ATF6、PERK、eIF2α、PEPCK、G6Pase mRNA水平较NC组增高(P<0.05),CREB、CRTC2、AKT mRNA水平较NC组降低(P<0.05);12周时,两组各观察指标差异无统计学意义。Pearson相关性分析显示(间歇低氧组第8周):胰岛素抵抗指数(HOMA-IR)与FoxO1、CREB、CRTC2及PERK、eIF2αmRNA水平呈正相关(r=0.172、0.595、0.183、0.702、0.608;P<0.05),与IRE1α、XBP1s、ATF6、AKT mRNA水平呈负相关(r=-0.422、-0.327、-0.309、-0.399;P<0.05)。结论间歇低氧可以导致胰岛素抵抗的发生,内质网应激可能介导了该效应的发生。

Objective To investigate the role of endoplasmic reticulum stress in hepatic insulin resistance induced by intermittent hypoxia in rats.Methods Twenty-four SD rats were randomly divided into control group(NC group)and intermittent hypoxia group(CIH group).The NC group was placed in a normoxia environment for 12 weeks,and the CIH group was given intermittent hypoxia for 8 weeks,and then returned to normoxia until the 12 th week.In both groups,fasting blood glucose(FBG),fasting insulin(FINS),and liver inositol-requiring enzyme-1α(IRE1α),X-box binding protein 1 s(XBP1 s),forkhead box transcription factor O1(FoxO1),activating transcription factor-6(ATF6),c AMP-response element binding protein(CREB),CREB-regulated transcription coactivator-2(CRTC2),double-stranded RNA-dependent protein kinase-like ER kinase(PERK),eukaryotic initiation factor 2α(e IF2α),protein kinase B(AKT),phosphoenolpyruvate carboxykinase(PEPCK),glucose-6-phosphatase(G6Pase)mRNA were measured at baseline,week 8,and week 12.Results There was no significant difference in each observation index between the two groups at baseline;at 8 weeks,the levels of FBG,FINS and the mRNA levels of IRE1α,XBP1s,ATF6,PERK,e IF2α,PEPCK and G6Pase in the CIH group were higher than those in the NC group(P<0.05),while the mRNA levels of CREB,CRTC2 and AKT were lower than those in the NC group(P<0.05);at 12 weeks,there was no significant difference in each observation index between the two groups.Pearson correlation analysis showed(8th week of intermittent hypoxia group):homeostasis model assessment-insulin resistance(HOMA-IR)was positively correlated with Fox O1,CREB,CRTC2 and PERK,e IF2αmRNA levels(r=0.172,0.595,0.183,0.702,0.608;P<0.05)while it was negatively correlated with IRE1α,XBP1s,ATF6,AKT mRNA levels(r=-0.422,-0.327,-0.309,-0.399;P<0.05).Conclusion Intermittent hypoxia can lead to insulin resistance,and endoplasmic reticulum stress may mediate this effect.