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颗粒蛋白前体(PGRN)最近被发现作为一种重要的调控子参与胰岛素抵抗的发生发展过程,然而其具体机制尚未阐明。在本研究中,给予PGRN和/或内质网应激抑制剂4-苯基丁酸(4-PBA)处理AML12肝细胞,运用免疫印迹分析,检测内质网应激标志物及胰岛素信号通路分子的表达。结果显示,PGRN可提高肝细胞eIF2α和PERK磷酸化的表达,降低IRS-1及Akt磷酸化的表达,表明PGRN可活化肝细胞内质网应激,损伤其胰岛素信号通路。同时,在PGRN干预的肝细胞中表现出上调的IL-6和TNF-α浓度,以及降低的葡萄糖摄取。此外,在PGRN处理的肝细胞中,内质网应激抑制剂4-PBA的加入可逆转PGRN的负效应。总之,我们的研究表明,PGRN作为一个重要的调控子,通过诱导内质网应激,损害胰岛素信号通路,导致肝细胞的胰岛素抵抗。
Abstract：Progranulin( PGRN) has recently been emerged as an important regulator for insulin resistance.However, the underlying mechanism involving the critical role of progranulin in insulin resistance was not fully understood. In this study, AML12 hepatocytes were treated with PGRN and/or endoplasmic reticulum(ER)stress inhibitor 4-phenylbutyric acid(4-PBA) for 20 h, and ER stress indicators and insulin signaling molecular were assessed by Western blotting. PGRN treatment in AML12 hepatocytes increased the phosphorylation of eIF2α and PERK, and reduced insulin-stimulated IRS-1 tyrosine phosphorylation and Akt Ser-473 phosphorylation,suggesting that PGRN induced activated ER stress and impaired insulin signaling. Meanwhile, AML12 hepatocytes treated with PGRN exhibited upregulation of IL-6 and TNF-α concentration in the medium and decreased glucose uptake. Additionally, inhibiting ER stress by addition of 4-PBA in PGRN-induced hepatocytes reversed the negative effect of PGRN. In conclusion, our findings supported the notion that PGRN is a key regulator of insulin resistance and that PGRN may impaired insulin signaling, at least in part, by inducing ER stress.
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基本信息:
DOI：10.13417/j.gab.035.003224
中图分类号:R587.1
引用信息:
[1]郭秦乐,徐琳,李会霞,等.颗粒蛋白前体(PGRN)通过活化内质网应激诱导肝细胞胰岛素抵抗的机制[J].基因组学与应用生物学,2016,35(12):3224-3230.DOI:10.13417/j.gab.035.003224.
基金信息:
国家自然科学基金(基金号:81500016)资助
2016-09-27
2016-09-27
2016-09-27