Karaskov Elizabeth, Scott Cameron, Zhang Liling, Teodoro Tracy, Ravazzola Mariella, Volchuk Allen
Division of Cell and Molecular Biology, Toronto General Research Institute, University Health Network, 200 Elizabeth Street, MBRC 4R402 Toronto, Ontario, Canada M5G 2C4.
Endocrinology. 2006 Jul;147(7):3398-407. doi: 10.1210/en.2005-1494. Epub 2006 Apr 6.
Chronic free fatty acid (FFA) exposure induces pancreatic beta-cell death, which may contribute to the development of type 2 diabetes. The mechanisms involved in FFA-induced cell death are not completely understood. Here we have investigated the effect of FFA on endoplasmic reticulum (ER) stress pathways in INS-1 pancreatic beta-cells. INS-1 cells exposed to palmitate for 16-24 h under serum-free conditions showed marked apoptosis and increased protein levels of phosphorylated eukaryotic translation initiation factor 2alpha (eIF2alpha), activating transcription factor 4 (ATF4), X box-binding protein 1 (XBP-1), and C/EBP homologous transcription factor (CHOP) compared with control cells. The CHOP transcription factor has been implicated in mediating ER stress-induced apoptosis. Unexpectedly, the levels of the ER chaperone proteins Grp78/BiP and PDI were not affected by palmitate treatment, suggesting that the cell protective aspects of the unfolded protein response (UPR) are not up-regulated by palmitate. Palmitate-treated cells had markedly altered distribution of ER chaperones and altered ER morphology, suggesting that accumulation of misfolded proteins might trigger the ER stress response. In contrast, oleate treatment did not significantly induce the UPR pathways, nor was it as detrimental to INS-1 beta-cells. The results suggest that activation of the UPR may significantly contribute to palmitate- but not oleate-induced pancreatic beta-cell death.
长期暴露于游离脂肪酸（FFA）会导致胰腺β细胞死亡，这可能促使2型糖尿病的发生。FFA诱导细胞死亡所涉及的机制尚未完全明确。在此，我们研究了FFA对INS-1胰腺β细胞内质网（ER）应激通路的影响。与对照细胞相比，在无血清条件下暴露于棕榈酸16 - 24小时的INS-1细胞显示出明显的凋亡，且磷酸化真核翻译起始因子2α（eIF2α）、激活转录因子4（ATF4）、X盒结合蛋白1（XBP-1）和C/EBP同源转录因子（CHOP）的蛋白水平升高。CHOP转录因子与介导ER应激诱导的凋亡有关。出乎意料的是，ER伴侣蛋白Grp78/BiP和PDI的水平不受棕榈酸处理的影响，这表明未折叠蛋白反应（UPR）的细胞保护方面未被棕榈酸上调。棕榈酸处理的细胞中ER伴侣蛋白的分布明显改变，ER形态也发生改变，这表明错误折叠蛋白的积累可能触发ER应激反应。相比之下，油酸处理并未显著诱导UPR通路，对INS-1β细胞的损害也较小。结果表明，UPR的激活可能显著促成棕榈酸而非油酸诱导的胰腺β细胞死亡。
