The role of ORMDL3/ATF6 in compensated beta cell proliferation during early diabetes
The role of ORMDL3/ATF6 in compensated beta cell proliferation during early diabetes
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ORMDL3/ATF6 在早期糖尿病补偿性 β 细胞增殖中的作用
DOI：
10.18632/aging.101949
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发表时间：
2019-05-15
期刊：
影响因子：
5.2
通讯作者：
Xiao, Xiangwei
中科院分区：
文献类型：
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作者：
Yang, Weixia;Sheng, Feifei;Xiao, Xiangwei
β细胞内质网（ER）应激诱导了一个称为未折叠蛋白反应（UPR）的信号网络，该信号网络在糖尿病中起双重作用。er应激和UPR的关键调节因子orosomucoid 1-like protein 3 （ORMDL3）已被证明通过一个主要的UPR蛋白激活转录因子6 （ATF6）调节气道重塑，但该调节轴对糖尿病代偿性胰腺β细胞增殖的贡献尚未被研究。在这里，我们检测到与正常儿童相比，1型糖尿病（T1D）儿童外周血标本白细胞中的ORMDL3 mRNA水平显著降低。此外，T1D儿童的ORMDL3水平在随访中进一步下降。NOD小鼠（人类T1D小鼠模型）胰岛中的ORMDL3水平在糖尿病发病前显示出轻度升高，但随后逐渐下降。在高糖培养中，ORMDL3水平的过度表达增加了β细胞的增殖，而不是凋亡，这可能是由其下游因子ATF6介导的。从机制上讲，ORMDL3转录激活了ATF6，这在启动子报告基因试验中得到了证实。总之，我们的数据表明ORMDL3可能通过ATF6增加β细胞增殖，作为糖尿病反应的早期代偿变化。
Endoplasmic reticulum (ER) stress in beta cells induces a signaling network called the unfolded protein response (UPR), which plays a dual role in diabetes. A key regulator of ER-stress and UPR, the orosomucoid 1-like protein 3 (ORMDL3), has been shown to regulate airway remodeling through a major UPR protein, activating transcription factor 6 (ATF6), but the contribution of this regulatory axis to compensatory pancreatic beta cell proliferation in diabetes has not been studied. Here, we detected significantly lower levels of ORMDL3 mRNA in leukocytes of peripheral blood specimens from type 1 diabetes (T1D) children, compared to normal children. Moreover, these ORMDL3 levels in T1D children exhibited further decreases upon follow-up. ORMDL3 levels in islets from NOD mice, a mouse model for T1D in humans, showed a mild increase before diabetes onset, but a gradual decrease subsequently. In high glucose culture, beta cell proliferation, but not apoptosis, was increased by overexpression of ORMDL3 levels, likely mediated by its downstream factor ATF6. Mechanistically, ORMDL3 transcriptionally activated ATF6, which was confirmed in a promoter reporter assay. Together, our data suggest that ORMDL3 may increase beta cell proliferation through ATF6 as an early compensatory change in response to diabetes.