Protective Role of Autophagy in Palmitate-Induced INS-1 β-Cell Death
Protective Role of Autophagy in Palmitate-Induced INS-1 β-Cell Death
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DOI：
10.1210/en.2008-0483
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发表时间：
2009-01-01
期刊：
影响因子：
4.8
通讯作者：
Kang, Yup
中科院分区：
文献类型：
--
作者：
Choi, Sung-E;Lee, Sung-Mi;Kang, Yup
自噬是一种液泡降解途径，是一种避免细胞死亡或消除细胞死亡替代途径的应激适应。本研究旨在确定自噬是否在棕榈酸酯（PA）处理的β细胞中被激活，以及如果被激活，自噬在PA诱导的β细胞死亡中的作用。在25 mM葡萄糖存在下，将INS-1 β细胞暴露于400 μ M PA 12小时，观察到自噬体和自溶酶体的形成增强。绿色荧光蛋白-LC 3-标记结构（绿色荧光蛋白-LC 3点）的形成以及从LC 3-I到LC 3-II的转化在PA处理的细胞中也是明显的。磷酸化哺乳动物雷帕霉素靶蛋白水平，一个典型的信号通路，抑制自噬的激活，逐渐减少PA治疗。通过用雷帕霉素处理来阻断哺乳动物雷帕霉素靶信号通路增强了自噬体的形成，但减少了PA诱导的INS-1细胞死亡。相反，通过敲低ATG 5减少自噬体形成，通过用巴弗洛霉素A1处理抑制自噬体和溶酶体之间的融合，或通过用E64 d/胃酶抑素A处理抑制蛋白水解降解，显著增强PA诱导的INS-1细胞死亡。这些结果表明，自噬系统可以激活PA处理的INS-1 β细胞，并建议诱导自噬可能发挥适应和保护作用，在PA诱导的细胞死亡。
Autophagy, a vacuolar degradative pathway, constitutes a stress adaptation that avoids cell death or elicits the alternative cell-death pathway. This study was undertaken to determine whether autophagy is activated in palmitate (PA)-treated beta-cells and, if activated, what the role of autophagy is in the PA-induced beta-cell death. The enhanced formation of autophagosomes and autolysosomes was observed by exposure of INS-1 beta-cells to 400 mu M PA in the presence of 25 mM glucose for 12 h. The formation of green fluorescent protein-LC3-labeled structures (green fluorescent protein-LC3 dots), with the conversion from LC3-I to LC3-II, was also distinct in the PA-treated cells. The phospho-mammalian target of rapamycin level, a typical signal pathway that inhibits activation of autophagy, was gradually decreased by PA treatment. Blockage of the mammalian target of rapamycin signaling pathway by treatment with rapamycin augmented the formation of autophagosomes but reduced PA-induced INS-1 cell death. In contrast, reduction of autophagosome formation by knocking down the ATG5, inhibition of fusion between autophagosome and lysosomeby treatment with bafilomycin A1, or inhibition of proteolytic degradation by treatment with E64d/pepstatin A, significantly augmented PA-induced INS-1 cell death. These findings showed that the autophagy system could be activated in PA-treated INS-1 beta-cells, and suggested that the induction of autophagy might play an adaptive and protective role in PA-induced cell death.