Free fatty acid induces endoplasmic reticulum stress and apoptosis of β-cells by Ca2+/calpain-2 pathways.
Free fatty acid induces endoplasmic reticulum stress and apoptosis of β-cells by Ca2+/calpain-2 pathways.
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DOI：
10.1371/journal.pone.0059921
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Ji Q
中科院分区：
文献类型：
--
作者：
Cui W;Ma J;Wang X;Yang W;Zhang J;Ji Q
β-细胞功能障碍是2型糖尿病（T2DM）发病机制的一个主要特征。肥胖合并T2DM与血浆游离脂肪酸（FFAs）升高有关。然而，将FFAs与β细胞功能障碍联系起来的分子机制仍然知之甚少。在本研究中，我们发现β-TC3细胞暴露于FFA后，主要内质网应激（ERS）标志物Grp78和ERS诱导的凋亡因子CHOP呈时间依赖性增加。在FFA处理后，ATF6的表达以及触发ERS信号的PERK和IRE1的磷酸化水平显著升高。FFA处理通过诱导β-TC3细胞ERS增加细胞凋亡。我们还发现，ffa诱导的ERS是通过促进STIM1和Orai1的关联，由储存操作的Ca2+进入介导的。此外，在β-TC3细胞中，ffa诱导CHOP的表达和caspase-12、caspase-3的激活需要calpain-2，从而促进细胞凋亡。总之，这些结果揭示了Ca2+/calpain-2通路在调节ffa诱导的β-TC3细胞ERS和凋亡中的关键作用。
Dysfunction of β-cells is a major characteristic in the pathogenesis of type 2 diabetes mellitus (T2DM). The combination of obesity and T2DM is associated with elevated plasma free fatty acids (FFAs). However, molecular mechanisms linking FFAs to β-cell dysfunction remain poorly understood. In the present study, we identified that the major endoplasmic reticulum stress (ERS) marker, Grp78 and ERS-induced apoptotic factor, CHOP, were time-dependently increased by exposure of β-TC3 cells to FFA. The expression of ATF6 and the phosphorylation levels of PERK and IRE1, which trigger ERS signaling, markedly increased after FFA treatments. FFA treatments increased cell apoptosis by inducing ERS in β-TC3 cells. We also found that FFA-induced ERS was mediated by the store-operated Ca2+ entry through promoting the association of STIM1 and Orai1. Moreover, calpain-2 was required for FFA-induced expression of CHOP and activation of caspase-12 and caspase-3, thus promoting cell apoptosis in β-TC3 cells. Together, these results reveal pivotal roles for Ca2+/calpain-2 pathways in modulating FFA-induced β-TC3 cell ERS and apoptosis.
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影响因子：
64.5
作者：
Park CY;Hoover PJ;Mullins FM;Bachhawat P;Covington ED;Raunser S;Walz T;Garcia KC;Dolmetsch RE;Lewis RS
通讯作者：
Lewis RS
影响因子：
5
作者：
Ceylan-Isik AF;Sreejayan N;Ren J
通讯作者：
Ren J
影响因子：
4
作者：
Fonseca, Sonya G.;Burcin, Mark;Gromada, Jesper;Urano, Fumihiko
通讯作者：
Urano, Fumihiko
影响因子：
8.2
作者：
GROMADA, J;DISSING, S;FROKJAERJENSEN, J
通讯作者：
FROKJAERJENSEN, J
影响因子：
4.8
作者：
ELKS, ML
通讯作者：
ELKS, ML