Ablation of C/EBPβ alleviates ER stress and pancreatic β cell failure through the GRP78 chaperone in mice
Ablation of C/EBPβ alleviates ER stress and pancreatic β cell failure through the GRP78 chaperone in mice
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DOI：
10.1172/jci39721
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发表时间：
2010-01-01
影响因子：
15.9
通讯作者：
Kasuga, Masato
中科院分区：
文献类型：
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作者：
Matsuda, Tomokazu;Kido, Yoshiaki;Kasuga, Masato
胰岛β细胞衰竭被认为是从葡萄糖耐受到明显的糖尿病进展的基础，而内质网应激与这种β细胞功能障碍有关。我们现在已经证明，在高血糖开始之前，由于内质网应激，转录因子CCAAT/增强子结合蛋白β(C/EBPβ)在糖尿病动物模型的胰岛中积累。转基因过表达的C/EBPβ基因在小鼠的β细胞中特异性地减少了β细胞质量，降低了血浆胰岛素水平，导致了糖尿病的发生。相反，基因切除糖尿病小鼠模型的β细胞中的C/EBPβ，包括在Ins2(WT/C96Y)和瘦素受体缺陷(LEPR(-/-))小鼠中存在杂合突变的秋田小鼠，导致β细胞质量增加和高血糖得到改善。由于转录因子ATF6α的反式激活活性被抑制，胰岛β细胞中C/EBPβ的积累减少了78 kDa的分子伴侣葡萄糖调节蛋白(GRP78)的丰度，从而增加了这些细胞对过度内质网应激的易感性。因此，我们的结果表明，C/EBPβ在胰岛β细胞中的积累通过增强对内质网应激的敏感性而导致小鼠胰岛β细胞衰竭。
Pancreatic beta cell failure is thought to underlie the progression from glucose intolerance to overt diabetes, and ER stress is implicated in such beta cell dysfunction. We have now shown that the transcription factor CCAAT/enhancer-binding protein beta (C/EBP beta) accumulated in the islets of diabetic animal models as a result of ER stress before the onset of hyperglycemia. Transgenic overexpression of C/EBP beta specifically in beta cells of mice reduced beta cell mass and lowered plasma insulin levels, resulting in the development of diabetes. Conversely, genetic ablation of C/EBP beta in the beta cells of mouse models of diabetes, including Akita mice, which harbor a heterozygous mutation in Ins2 (Ins2(WT/C96Y)), and leptin receptor-deficient (Lepr(-/-)) mice, resulted in an increase in beta cell mass and ameliorated hyperglycemia. The accumulation of C/EBP beta in pancreatic beta cells reduced the abundance of the molecular chaperone glucose-regulated protein of 78 kDa (GRP78) as a result of suppression of the transactivation activity of the transcription factor ATF6 alpha, thereby increasing the vulnerability of these cells to excess ER stress. Our results thus indicate that the accumulation of C/EBP beta in pancreatic beta cells contributes to beta cell failure in mice by enhancing susceptibility to ER stress.