Restoration of the unfolded protein response in pancreatic β cells protects mice against type 1 diabetes.
Restoration of the unfolded protein response in pancreatic β cells protects mice against type 1 diabetes.
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DOI：
10.1126/scitranslmed.3006534
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发表时间：
2013-11-13
影响因子：
17.1
通讯作者：
Hotamisligil GS
中科院分区：
文献类型：
--
作者：
Engin F;Yermalovich A;Nguyen T;Hummasti S;Fu W;Eizirik DL;Mathis D;Hotamisligil GS
内质网（ER）稳态的扰动可以引起应激反应，导致糖和脂质代谢异常。ER功能障碍与炎症性疾病有关，但其在自身免疫性1型糖尿病（T1D）发病机制中的作用仍不清楚。我们在来自两种不同T1D小鼠模型的β细胞中鉴定了未折叠蛋白反应（UPR）介导物ATF6（转录激活因子6）和XBP1（X盒结合蛋白1）的表达缺陷，然后在来自T1D患者的胰腺β细胞中证明了类似的缺陷。在糖尿病前期阶段给予化学ER应激缓解剂牛磺熊去氧胆酸（TUDCA）导致T1D小鼠模型中糖尿病发病率显著降低。这种减少伴随着（i）胰腺中侵袭性淋巴细胞浸润的显著减少，（ii）β细胞的存活和形态改善，（iii）β细胞凋亡减少，（iv）胰岛素分泌保留，以及（v）UPR介质的表达恢复。TUDCA的作用依赖于ATF6，在β细胞特异性缺失ATF6的小鼠中TUDCA的作用丧失。这些数据表明，UPR的适当维持对于β细胞的保存是必不可少的，并且该过程中的缺陷可以通过化学方法恢复，用于T1D的预防性或治疗性干预。
Perturbations in endoplasmic reticulum (ER) homeostasis can evoke stress responses leading to aberrant glucose and lipid metabolism. ER dysfunction is linked to inflammatory disorders, but its role in the pathogenesis of autoimmune type 1 diabetes (T1D) remains unknown. We identified defects in the expression of unfolded protein response (UPR) mediators ATF6 (activating transcription factor 6) and XBP1 (X-box binding protein 1) in β cells from two different T1D mouse models and then demonstrated similar defects in pancreatic β cells from T1D patients. Administration of a chemical ER stress mitigator, tauroursodeoxycholic acid (TUDCA), at the prediabetic stage resulted in a marked reduction of diabetes incidence in the T1D mouse models. This reduction was accompanied by (i) a significant decrease in aggressive lymphocytic infiltration in the pancreas, (ii) improved survival and morphology of β cells, (iii) reduced β cell apoptosis, (iv) preserved insulin secretion, and (v) restored expression of UPR mediators. TUDCA′s actions were dependent on ATF6 and were lost in mice with β cell-specific deletion of ATF6. These data indicate that proper maintenance of the UPR is essential for the preservation of β cells and that defects in this process can be chemically restored for preventive or therapeutic interventions in T1D.
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影响因子：
82.9
作者：
Erbay, Ebru;Babaev, Vladimir R.;Mayers, Jared R.;Makowski, Liza;Charles, Khanichi N.;Snitow, Melinda E.;Fazio, Sergio;Wiest, Michelle M.;Watkins, Steven M.;Linton, MacRae F.;Hotamisligil, Goekhan S.
通讯作者：
Hotamisligil, Goekhan S.
影响因子：
16
作者：
Harding, HP;Zhang, YH;Ron, D
通讯作者：
Ron, D
人类胰岛素基因的七种突变与永久性新生儿/婴幼儿糖尿病有关
影响因子：
15.9
作者：
Colombo, Carlo;Porzio, Ottavia;Barbetti, Fabrizio
通讯作者：
Barbetti, Fabrizio
影响因子：
4
作者：
Fonseca, Sonya G.;Burcin, Mark;Gromada, Jesper;Urano, Fumihiko
通讯作者：
Urano, Fumihiko
影响因子：
64.5
作者：
OLDSTONE, MBA;NERENBERG, M;LEWICKI, H
通讯作者：
LEWICKI, H