Clock Gene Dysregulation Induced by Chronic ER Stress Disrupts β-cell Function.
Clock Gene Dysregulation Induced by Chronic ER Stress Disrupts β-cell Function.
复制标题
DOI：
10.1016/j.ebiom.2017.03.040
复制
发表时间：
2017-04
期刊：
影响因子：
11.1
通讯作者：
Tanizawa Y
中科院分区：
文献类型：
--
作者：
Ohta Y;Taguchi A;Matsumura T;Nakabayashi H;Akiyama M;Yamamoto K;Fujimoto R;Suetomi R;Yanai A;Shinoda K;Tanizawa Y
在 Wfs1−/−Ay/a 胰岛中，与内质网 (ER) 应激相关，D 位点结合蛋白 (Dbp) 表达减少，核因子 IL-3 (Nfil3)/E4 启动子结合蛋白 4 (E4bp4) 表达增加，导致 DBP 转录活性降低。化学诱导的内质网应激也观察到类似的变化。在小鼠胰岛素 I 基因启动子 (MIP) 的控制下表达 E4BP4 的转基因小鼠，其中 β 细胞中的 E4BP4 预计会与 DBP 竞争 D-box，表现出明显的葡萄糖不耐受，胰岛素分泌严重受损。 MIP-E4BP4 胰岛中的基础 ATP/ADP 比率升高，但没有在野生型胰岛中观察到昼夜节律振荡。葡萄糖刺激后，既没有观察到 ATP/ADP 比率的升高，也没有观察到细胞内 Ca2+ 反应。在野生型胰岛中，与胰岛素分泌相关的基因的RNA表达在喂养期早期逐渐增加。然而，在 MIP-E4BP4 胰岛中，没有观察到这些增加。因此，分子钟输出的 DBP 转录活性易受 ER 应激影响，通过调节 β 细胞代谢和基因表达，在 β 细胞启动胰岛素释放中发挥关键作用。由于 ER 应激还与更常见的 2 型糖尿病中的 β 细胞衰竭有关，因此了解目前确定的 ER 应激相关机制需要针对罕见糖尿病和常见糖尿病采取新的治疗和预防策略。 ER 应激会降低 DBP 并增加 E4BP4 表达，从而减少 DBP 转录活性的总体降低。 DBP 的组成性抑制会损害基础 ATP/ADP 比率的昼夜节律振荡，并改变胰岛中的基因表达。内质网应激与糖尿病β细胞功能障碍相关的分子钟输出之间存在着至关重要的联系。 Wolfram 综合征是一种由 WFS1 突变引起的罕见遗传病，它提供了 ER 应激、β 细胞衰竭和糖尿病之间的联系。内质网应激显着降低了时钟输出基因 DBP 的转录活性。抑制β细胞中的DBP转录活性可通过调节β细胞代谢和参与胰岛素分泌的基因表达来严重减少体内胰岛素分泌。 β 细胞 ER 应激不仅是由 WFS1 突变引起的，而且在常见的 2 型糖尿病 (T2DM) 中也会通过糖脂毒性等机制引起。调节 β 细胞时钟基因可以成为预防和治疗 Wolfram 综合征和 T2DM 中 β 细胞衰竭的治疗靶标。
In Wfs1−/−Ay/a islets, in association with endoplasmic reticulum (ER) stress, D-site-binding protein (Dbp) expression decreased and Nuclear Factor IL-3 (Nfil3)/E4 Promoter-binding protein 4 (E4bp4) expression increased, leading to reduced DBP transcriptional activity. Similar alterations were observed with chemically-induced ER stress. Transgenic mice expressing E4BP4 under the control of the mouse insulin I gene promoter (MIP), in which E4BP4 in β-cells is expected to compete with DBP for D-box, displayed remarkable glucose intolerance with severely impaired insulin secretion. Basal ATP/ADP ratios in MIP-E4BP4 islets were elevated without the circadian oscillations observed in wild-type islets. Neither elevation of the ATP/ADP ratio nor an intracellular Ca2 + response was observed after glucose stimulation. RNA expressions of genes involved in insulin secretion gradually increase in wild-type islets early in the feeding period. In MIP-E4BP4 islets, however, these increases were not observed. Thus, molecular clock output DBP transcriptional activity, susceptible to ER stress, plays pivotal roles in β-cell priming for insulin release by regulating β-cell metabolism and gene expressions. Because ER stress is also involved in the β-cell failure in more common Type-2 diabetes, understanding the currently identified ER stress-associated mechanisms warrants novel therapeutic and preventive strategies for both rare form and common diabetes. ER stress decreases DBP and increases E4BP4 expressions, reducing overall reduction of DBP transcriptional activity. Constitutive suppression of DBP impairs circadian oscillation of basal ATP/ADP ratio and alters gene expressions in islets. There is a crucial link between ER stress and molecular clock output involved in β-cell dysfunction in diabetes. Wolfram syndrome, a rare genetic disease caused by the WFS1 mutation, provides a link between ER stress, β-cell failure, and diabetes. ER stress remarkably reduced the transcriptional activity of DBP, a clock out-put gene. Suppression of DBP transcriptional activity in β-cells severely reduced insulin secretion in vivo by regulating β-cell metabolism and gene expressions involved in insulin secretion. β-cell ER stress is induced not only by WFS1 mutations but also in common form type-2 diabetes (T2DM) by mechanisms such as glucoliptoxicity. Modulating of β-cell clock genes can be therapeutic targets preventing and remedying β-cell failure in Wolfram syndrome and T2DM.