内质网应激调节肝星状细胞HGF表达的作用机制
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国家自然科学基金(81070380);江苏省自然科学基金(BK20131445);国家卫计委行业基金(20132009)


Mechanism of HGF expression regulated by endoplasmic reticulum stress in hepatic stellate cells
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    摘要:

    目的:探讨内质网应激对肝星状细胞分泌肝细胞生长因子(hypatocyte growth factor,HGF)的影响及其可能机制。方法: 通过在培养的大鼠肝星状细胞T6中分别加入5.0 -滋g/mL衣霉素或0.2 -滋mol/L毒胡萝卜素建立肝星状细胞内质网应激模型,4.0 mmol/L 4-苯基丁酸钠(4-phenylbutyrate,4-PBA)和200.0 -滋mol/L salubrinal作为内质网应激抑制剂对T6细胞进行预处理,重组慢病毒LV-eIf2α-shRNA-GFP敲减T6细胞中的 eIf2α mRNA表达,并提取mRNA和全蛋白进行RT-PCR和Western blot实验检测HGF-分子伴侣重链结合蛋白(glucose-regulated protein 78,GRP78)-真核翻译起始因子2α(eukaryotic translation initiation factor 2α,eIf2α)-磷酸化eIf2α-激活转录因子4(activating transcription factor 4,ATF4)以及凋亡信号分子C/EBP同源蛋白(C/EBP homologous protein,CHOP)。结果:衣霉素-毒胡萝卜素可诱导T6细胞GRP78升高,激活内质网应激状态的同时抑制HGF表达,4-PBA和salubrinal可阻止内质网应激引起的HGF降低,但对ATF4和CHOP的表达作用不同。慢病毒转染T6降低细胞eIf2α表达的同时成比例降低HGF表达。结论:ERS激活后可通过影响eIf2α表达从而抑制HGF表达。

    Abstract:

    Objective: To detect whether suppression of endoplasmic reticulum (ER) stress maintains hepatocyte growth factor (HGF) expression in hepatic stellate cells (HSCs) and its potential mechanism. Methods: Rat hepatic stellate cell line HSC-T6 was treated with the ER stress agonists 5.0 -滋g/mL tunicamycin and 0.2 -滋mol/L thapsigargin, and ER stress inhibitors sodium 4-phenylbutyrate (4-PBA) 4.0 mmol/L and salubrinal 200.0 -滋mol/L were used as pretreatment. Recombinant lentivirus LV-eIf2α-shRNA-GFP was produced to block eIf2α activated by ER stress. Levels of HGF, glucose-regulated protein 78 (GRP78), eukaryotic translation initiation factor 2α (eIf2α), phospho-eIF2α, activating transcription factor 4(ATF4) and C/EBP (CCAAT/enhancer binding protein) homologous protein (CHOP) in vitro were measured by quantitative RT-PCR and Western blot. Results: Our results demonstrated that tunicamycin or thapsigargin stimulated GRP78 expression, and activation of ER stress inhibited HGF expression in HSC-T6 cells. The inhibition of HGF could be partly prevented in the presence of 4-PBA or salubrinal, but their effects on ATF4 and CHOP expression were different. Interfering eIf2α mRNA proportionately down-regulated HGF expression. Conclusion: The activation of ER stress inhibits HGF expression of HSCs through decreasing eIF2α expression.

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刘雨亭,李 书,陈建亮,周 澍,曹守纪,俞 悦,李国强.内质网应激调节肝星状细胞HGF表达的作用机制[J].南京医科大学学报(自然科学版),2016,(9):1046-1051

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  • 在线发布日期: 2016-09-18
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