Glucotoxicity-induced suppression of Cox6a2 expression provokes β-cell dysfunction via augmented ROS production
Glucotoxicity-induced suppression of Cox6a2 expression provokes β-cell dysfunction via augmented ROS production
复制标题
DOI：
10.1016/j.bbrc.2021.03.148
复制
发表时间：
2021-04-08
影响因子：
3.1
通讯作者：
Shimomura, Iichiro
中科院分区：
文献类型：
--
作者：
Nagai, Yasuki;Matsuoka, Taka-aki;Shimomura, Iichiro
氧化应激是糖尿病慢性高血糖患者胰腺β细胞恶化的一个因素。然而，糖尿病条件下β细胞氧化应激增加的分子机制尚不清楚。我们之前已经证明，选择性减轻糖毒性可以改善几种β细胞因子的下调，包括Cox6a2。Cox6a2编码线粒体呼吸链复合体IV的一个亚基。在本研究中，我们分析了Cox6a2在糖尿病患者胰腺β细胞功能中的作用及其病理生理意义。在MIN6-CB4细胞中进行的cox 6a2敲低实验表明，CellROX Deep Red试剂使用流式细胞术检测到活性氧的产生增加。在全身性敲除cox6a2的小鼠中，在高脂高糖饮食下观察到糖耐量受损。然而，与对照组相比，胰岛素抵抗降低了。这表明β细胞功能相对不足。为了研究Cox6a2的转录调控，我们对胰岛DNA进行了ATAC-seq，并在Cox6a2增强子区域检测到一个开放的染色质区域。利用该区域进行报告基因分析发现，MafA直接调控Cox6a2的表达。这些发现表明，Cox6a2表达的降低增加了活性氧的水平，并且在糖中毒条件下，Mafa与Cox6a2表达的降低有关。(C) 2021爱思唯尔公司版权所有。
Oxidative stress is a deteriorating factor for pancreatic beta-cells under chronic hyperglycemia in diabetes. However, the molecular mechanism underlying the increase in oxidative stress in beta-cells under diabetic conditions remains unclear. We demonstrated previously that the selective alleviation of glucotoxicity ameliorated the downregulation of several beta-cell factors, including Cox6a2. Cox6a2 encodes a subunit of the respiratory chain complex IV in mitochondria. In this study, we analyzed the role of Cox6a2 in pancreatic beta-cell function and its pathophysiological significance in diabetes mellitus. Cox6a2-knockdown experiments in MIN6-CB4 cells indicated an increased production of reactive oxygen species as detected by CellROX Deep Red reagent using flow cytometry. In systemic Cox6a2-knockout mice, impaired glucose tolerance was observed under a high-fat high-sucrose diet. However, insulin resistance was reduced when compared with control littermates. This indicates a relative insufficiency of beta-cell function. To examine the transcriptional regulation of Cox6a2, ATAC-seq with islet DNA was performed and an open-chromatin area within the Cox6a2 enhancer region was detected. Reporter gene analysis using this area revealed that MafA directly regulates Cox6a2 expression. These findings suggest that the decreased expression of Cox6a2 increases the levels of reactive oxygen species and that Mafa is associated with decreased Cox6a2 expression under glucotoxic conditions. (C) 2021 Elsevier Inc. All rights reserved.