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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。
Progranulin (PGRN) has recently been found to play an important regulatory role in the development of insulin resistance, but its exact mechanism has not been elucidated yet. In this study, AML12 hepatocytes were treated with PGRN and / or endoplasmic reticulum stress inhibitor 4-phenylbutyrate (4-PBA), and Western blot analysis was performed to detect endoplasmic reticulum stress markers and insulin signaling Expression of molecules. The results showed that PGRN could enhance the phosphorylation of eIF2alpha and PERK in hepatocytes and decrease the phosphorylation of IRS-1 and Akt, indicating that PGRN can activate the endoplasmic reticulum stress of hepatocytes and impair the insulin signaling pathway. At the same time, elevated concentrations of IL-6 and TNF-α were shown in PGRN-treated hepatocytes as well as decreased glucose uptake. In addition, the addition of endoplasmic reticulum stress inhibitor 4-PBA reverses the negative effect of PGRN in PGRN-treated hepatocytes. In conclusion, our study shows that PGRN acts as an important regulator by inducing endoplasmic reticulum stress that impairs insulin signaling and leads to hepatocyte insulin resistance.