Involvement of dynamin-related protein 1 in free fatty acid-induced INS-1-derived cell apoptosis.
Involvement of dynamin-related protein 1 in free fatty acid-induced INS-1-derived cell apoptosis.
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动力相关蛋白 1 参与游离脂肪酸诱导的 INS-1 衍生细胞凋亡
DOI：
10.1371/journal.pone.0049258
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Lou J
中科院分区：
文献类型：
--
作者：
Peng L;Men X;Zhang W;Wang H;Xu S;Fang Q;Liu H;Yang W;Lou J
细胞外游离脂肪酸（FFA）升高可诱导胰腺β细胞凋亡，从而促进2型糖尿病（T2D）的发病机制。线粒体功能障碍与 FFA 诱导的 β 细胞凋亡有关。然而，线粒体功能障碍和 FFA 诱导的 β 细胞凋亡之间的分子机制尚不清楚。动力相关蛋白 1 (DRP-1) 是一种线粒体裂变调节剂。在这项研究中，我们研究了它在 FFA 诱导的 INS-1 β 细胞凋亡中的作用。 FFA刺激后，INS-1细胞和大鼠胰岛中的DRP-1蛋白迅速被诱导，并且DRP-1的上调伴随着INS-1细胞凋亡的增加。在 DRP-1 WT（DRP-1 野生型）诱导型 INS-1 衍生细胞系中，诱导 DRP-1 表达显着促进 FFA 诱导的细胞凋亡，但在 DRP-1K38A（DRP-1 的显性失活突变体）诱导型 INS-1 衍生细胞系中则不然。为了验证这些体外结果，我们将 DRP-1 WT 或 DRP-1 K38A 细胞移植到链脲佐菌素 (STZ) 治疗的糖尿病小鼠的肾囊中，以研究异种移植物中的细胞凋亡。与体外结果一致，DRP-1 的过度表达导致 FFA 引发的 INS-1 衍生细胞凋亡加剧。相反，以 DRP-1 K38A 为代表的 DRP-1 功能的显性失活抑制显着阻止了异种移植物中 FFA 诱导的细胞凋亡。进一步证明，在 FFA 刺激下 INS-1 衍生细胞中，线粒体膜电位降低，而 DRP-1WT 的诱导增强了细胞色素 c 的释放、caspase-3 的激活和活性氧 (ROS) 的产生，但被 DRP-1 K38A 阻止。这些结果表明，DRP-1 介导 FFA 诱导的 INS-1 衍生细胞凋亡，表明抑制 DRP-1 是一种潜在有用的治疗策略，可防止导致 2 型糖尿病的 β 细胞丢失。
Elevated extracellular free fatty acids (FFAs) can induce pancreatic beta cell apoptosis, thereby contributing to the pathogenesis of type 2 diabetes mellitus (T2D). Mitochondrial dysfunction has been implicated in FFA-induced beta cell apoptosis. However, molecular mechanisms linking mitochondrial dysfunction and FFA-induced beta cell apoptosis are not clear. Dynamin-related protein 1 (DRP-1) is a mitochondrial fission modulator. In this study, we investigated its role in FFA-induced INS-1 beta cell apoptosis. DRP-1 protein was promptly induced in INS-1 cells and rat islets after stimulation by FFAs, and this DRP-1 upregulation was accompanied by increased INS-1 cell apoptosis. Induction of DRP-1 expression significantly promoted FFA-induced apoptosis in DRP-1 WT (DRP-1 wild type) inducible INS-1-derived cell line, but not in DRP-1K38A (a dominant negative mutant of DRP-1) inducible INS-1-derived cell line. To validate these in vitro results, we transplanted DRP-1 WT or DRP-1 K38A cells into renal capsules of streptozotocin (STZ)-treated diabetic mice to study the apoptosis in xenografts. Consistent with the in vitro results, the over-expression of DRP-1 led to aggravated INS-1-derived cell apoptosis triggered by FFAs. In contrast, dominant-negative suppression of DRP-1 function as represented by DRP-1 K38A significantly prevented FFA-induced apoptosis in xenografts. It was further demonstrated that mitochondrial membrane potential decreased, while cytochrome c release, caspase-3 activation, and generation of reactive oxygen species (ROS) were enhanced by the induction of DRP-1WT, but prevented by DRP-1 K38A in INS-1-derived cells under FFA stimulation. These results indicated that DRP-1 mediates FFA-induced INS-1-derived cell apoptosis, suggesting that suppression of DRP-1 is a potentially useful therapeutic strategy for protecting against beta cell loss that leads to type 2 diabetes.
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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：
4
作者：
Mao, Jianning;Luo, Hongyu;Wui, Jiangping
通讯作者：
Wui, Jiangping
影响因子：
6.5
作者：
Ravnskjaer, Kim;Frigerio, Francesca;Mandrup, Susanne
通讯作者：
Mandrup, Susanne
影响因子：
4.8
作者：
Chu, Kwan Yi;Lin, Yalin;Johnson, James D.
通讯作者：
Johnson, James D.
影响因子：
12.4
作者：
Martinou, J-C;Youle, R. J.
通讯作者：
Youle, R. J.