Chop deletion reduces oxidative stress, improves β cell function, and promotes cell survival in multiple mouse models of diabetes
Chop deletion reduces oxidative stress, improves β cell function, and promotes cell survival in multiple mouse models of diabetes
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DOI：
10.1172/jci34587
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发表时间：
2008-10-01
影响因子：
15.9
通讯作者：
Kaufman, Randal J.
中科院分区：
文献类型：
--
作者：
Song, Benbo;Scheuner, Donalyn;Kaufman, Randal J.
从胰岛素抵抗到2型糖尿病的进展是由于胰腺细胞不能产生足够水平的胰岛素来满足代谢需求。最近的研究表明，营养波动和胰岛素抵抗增加了β细胞中胰岛素原的合成，超过了内质网（ER）管腔内新生多肽的折叠能力，从而破坏内质网的稳态并引发未折叠蛋白反应（UPR）。慢性内质网应激促进细胞凋亡，至少部分是通过upr诱导的转录因子C/EBP同源蛋白（CHOP）。我们评估了Chop缺失对多种2型糖尿病小鼠模型的影响，发现Chop（-/-）小鼠在所有分析条件下都改善了血糖控制并扩大了β细胞质量。在遗传和饮食诱导的胰岛素抵抗模型中，CHOP缺乏可改善β细胞超微结构，促进细胞存活。此外，我们发现从Chop（-/-）小鼠中分离的胰岛显示出UPR和氧化应激反应基因的表达增加，氧化损伤水平降低。这些发现表明，在胰岛素需求增加的情况下，CHOP是将内质网蛋白错误折叠与β细胞氧化应激和凋亡联系起来的一个基本因素。
The progression from insulin resistance to type 2 diabetes is caused by the failure of pancreatic beta cells to produce sufficient levels of insulin to meet the metabolic demand. Recent studies indicate that nutrient fluctuations and insulin resistance increase proinsulin synthesis in beta cells beyond the capacity for folding of nascent polypeptides within the endoplasmic reticulum (ER) lumen, thereby disrupting ER homeostasis and triggering the unfolded protein response (UPR). Chronic ER stress promotes apoptosis, at least in part through the UPR-induced transcription factor C/EBP homologous protein (CHOP). We assessed the effect of Chop deletion in multiple mouse models of type 2 diabetes and found that Chop(-/-) mice had improved glycemic control and expanded beta cell mass in all conditions analyzed. In both genetic and diet-induced models of insulin resistance, CHOP deficiency improved beta cell ultrastructure and promoted cell survival. In addition, we found that isolated islets from Chop(-/-) mice displayed increased expression of UPR and oxidative stress response genes and reduced levels of oxidative damage. These findings suggest that CHOP is a fundamental factor that links protein mis-folding in the ER to oxidative stress and apoptosis in beta cells under conditions of increased insulin demand.