Endoplasmic Reticulum Stress-Induced CHOP Inhibits PGC-1α and Causes Mitochondrial Dysfunction in Diabetic Embryopathy
Endoplasmic Reticulum Stress-Induced CHOP Inhibits PGC-1α and Causes Mitochondrial Dysfunction in Diabetic Embryopathy
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DOI：
10.1093/toxsci/kfx096
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发表时间：
2017-08-01
影响因子：
3.8
通讯作者：
Yang, Peixin
中科院分区：
文献类型：
--
作者：
Chen, Xi;Zhong, Jianxiang;Yang, Peixin
内质网（ER）应激与母体糖尿病诱导的神经管缺陷（NTDs）的发生有关。ER应激诱导的C/EBP同源蛋白（CHOP）在促凋亡执行通路中起重要作用。然而，ER应激和CHOP诱导的糖尿病胚胎病神经上皮细胞凋亡的分子机制尚不清楚。Chop基因的缺失显著降低了母体糖尿病诱导的NTD。CHOP缺乏可消除母体糖尿病诱导的线粒体功能障碍和神经上皮细胞凋亡。进一步的分析表明，CHOP抑制过氧化物酶体增殖物激活受体-γ共激活因子-1 α（PGC-1 α）的表达，PGC-1 α是线粒体生物发生和功能的重要调节因子。体内CHOP缺陷和体外敲低均可恢复高糖抑制的PGC-1 α表达。相比之下，CHOP过表达模拟高糖对PGC-1 α的抑制。作为对内质网应激诱导剂衣霉素的响应，PGC-1 α表达降低，而内质网应激抑制剂4-苯基丁酸阻断高糖抑制的PGC-1 α表达。此外，体内母体糖尿病和体外高糖促进CHOP和PGC-1 α转录调节因子CCAAT/增强子结合蛋白-β（C/EBP β）之间的相互作用，并降低C/EBP β与PGC-1 α启动子的结合，导致PGC-1 α表达显著降低。总之，我们的研究结果支持这样的假设，即母体糖尿病诱导的ER应激增加CHOP表达，CHOP表达通过抑制C/EBPb转录活性来抑制PGC-1 α，随后诱导线粒体功能障碍并最终导致NTD。
Endoplasmic reticulum (ER) stress has been implicated in the development of maternal diabetes-induced neural tube defects (NTDs). ER stress-induced C/EBP homologous protein (CHOP) plays an important role in the pro-apoptotic execution pathways. However, the molecular mechanism underlying ER stress- and CHOP-induced neuroepithelium cell apoptosis in diabetic embryopathy is still unclear. Deletion of the Chop gene significantly reduced maternal diabetes-induced NTDs. CHOP deficiency abrogated maternal diabetes-induced mitochondrial dysfunction and neuroepithelium cell apoptosis. Further analysis demonstrated that CHOP repressed the expression of peroxisome-proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha), an essential regulator for mitochondrial biogenesis and function. Both CHOP deficiency in vivo and knockdown in vitro restore high glucose-suppressed PGC-1 alpha expression. In contrast, CHOP overexpression mimicked inhibition of PGC-1 alpha by high glucose. In response to the ER stress inducer tunicamycin, PGC-1 alpha pression was decreased, whereas the ER stress inhibitor 4-phenylbutyric acid blocked high glucose-suppressed PGC-1 alpha expression. Moreover, maternal diabetes in vivo and high glucose in vitro promoted the interaction between CHOP and the PGC-1 alpha transcriptional regulator CCAAT/enhancer binding protein-beta (C/EBP beta), and reduced C/EBP beta binding to the PGC-1 alpha promoter leading to markedly decrease in PGC-1 alpha expression. Together, our findings support the hypothesis that maternal diabetes-induced ER stress increases CHOP expression which represses PGC-1 alpha through suppressing the C/EBPb transcriptional activity, subsequently induces mitochondrial dysfunction and ultimately results in NTDs.