Spontaneous Development of Endoplasmic Reticulum Stress That Can Lead to Diabetes Mellitus Is Associated with Higher Calcium-independent Phospholipase A2 Expression A ROLE FOR REGULATION BY SREBP-1
Spontaneous Development of Endoplasmic Reticulum Stress That Can Lead to Diabetes Mellitus Is Associated with Higher Calcium-independent Phospholipase A2 Expression A ROLE FOR REGULATION BY SREBP-1
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DOI：
10.1074/jbc.m109.084293
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发表时间：
2010-02-26
影响因子：
4.8
通讯作者：
Ramanadham, Sasanka
中科院分区：
文献类型：
--
作者：
Lei, Xiaoyong;Zhang, Sheng;Ramanadham, Sasanka
我们最近的研究表明，内质网（ER）应激通过Ca 2+非依赖性磷脂酶A（2）（iPLA（2）β）介导的机制引起INS-1细胞凋亡，该机制通过鞘磷脂水解促进神经酰胺生成，随后激活内源性途径。为了阐明iPLA（2）β和ER应激之间的关联，我们比较了野生型（WT）和秋田小鼠产生的β细胞系。秋田小鼠是ER应激的自发模型，其由于ER应激诱导的β细胞凋亡而发展高血糖症/糖尿病。与发展ER应激的倾向一致，基础磷酸化PERK和活化半胱天冬酶-3在秋田细胞中比WT细胞中更高。有趣的是，与WT细胞相比，秋田细胞中基础iPLA（2）β、成熟SREBP-1（mSREBP-1）、磷酸化Akt和中性鞘磷脂酶（NSMase）较高，鞘磷脂的相对丰度较低，线粒体膜电位（Delta Psi）受损。暴露于毒胡萝卜素加速秋田细胞的Delta Psi损失和凋亡，并且与WT和秋田细胞中iPLA（2）β、mSREBP-1和NSMase的增加相关。然而，用iPLA（2）β小干扰RNA转染秋田细胞，抑制了NSMase信息、Δ Psi丢失和凋亡。iPLA（2）β基因含有固醇调节元件，用显性负性SREBP-1转染可降低秋田细胞中的基础mSREBP-1和iPLA（2）β，并抑制毒胡萝卜素引起的mSREBP-1和iPLA（2）β增加。这些发现表明，ER应激导致mSREBP-1的产生，mSREBP-1可以结合iPLA（2）β基因中的固醇调节元件以促进其转录。与此一致，秋田小鼠胰岛中的SREBP-1、iPLA（2）β和NSMase信息高于WT胰岛。
Our recent studies indicate that endoplasmic reticulum (ER) stress causes INS-1 cell apoptosis by a Ca2+-independent phospholipase A(2) (iPLA(2)beta)-mediated mechanism that promotes ceramide generation via sphingomyelin hydrolysis and subsequent activation of the intrinsic pathway. To elucidate the association between iPLA(2)beta and ER stress, we compared beta-cell lines generated from wild type (WT) and Akita mice. The Akita mouse is a spontaneous model of ER stress that develops hyperglycemia/diabetes due to ER stress-induced beta-cell apoptosis. Consistent with a predisposition to developing ER stress, basal phosphorylated PERK and activated caspase-3 are higher in the Akita cells than WT cells. Interestingly, basal iPLA(2)beta, mature SREBP-1 (mSREBP-1), phosphorylated Akt, and neutral sphingomyelinase (NSMase) are higher, relative abundances of sphingomyelins are lower, and mitochondrial membrane potential (Delta Psi) is compromised in Akita cells, in comparison with WT cells. Exposure to thapsigargin accelerates Delta Psi loss and apoptosis of Akita cells and is associated with increases in iPLA(2)beta, mSREBP-1, and NSMase in both WT and Akita cells. Transfection of Akita cells with iPLA(2)beta small interfering RNA, however, suppresses NSMase message, Delta Psi loss, and apoptosis. The iPLA(2)beta gene contains a sterol-regulatory element, and transfection with a dominant negative SREBP-1 reduces basal mSREBP-1 and iPLA(2)beta in the Akita cells and suppresses increases in mSREBP-1 and iPLA(2)beta due to thapsigargin. These findings suggest that ER stress leads to generation of mSREBP-1, which can bind to the sterol-regulatory element in the iPLA(2)beta gene to promote its transcription. Consistent with this, SREBP-1, iPLA(2)beta, and NSMase messages in Akita mouse islets are higher than in WT islets.