Pancreatic β-Cell O-GlcNAc Transferase Overexpression Increases Susceptibility to Metabolic Stressors in Female Mice.
Pancreatic β-Cell O-GlcNAc Transferase Overexpression Increases Susceptibility to Metabolic Stressors in Female Mice.
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DOI：
10.3390/cells10102801
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发表时间：
2021-10-19
期刊：
影响因子：
6
通讯作者：
Alejandro EU
中科院分区：
文献类型：
--
作者：
Mohan R;Jo S;Da Sol Chung E;Oribamise E;Lockridge A;Abrahante-Lloréns JE;Ruan HB;Yang XY;Alejandro EU
营养传感器O - 连接的N - 乙酰氨基葡萄糖转移酶（Ogt）是唯一能将O - GlcNAc修饰添加到蛋白质上的酶，它对胰腺β细胞的存活和胰岛素分泌起着关键作用。我们假设β细胞中Ogt的过表达能够保护β细胞，使其在面对诸如高脂饮食（HFD）和链脲佐菌素（STZ）等代谢应激源时不致功能衰竭。在此，我们构建了β细胞特异性过表达Ogt的（βOgtOE）小鼠，在正常饲料喂养下，观察到胰岛中Ogt蛋白水平以及蛋白质的O - GlcNAc修饰显著增加。我们发现，在正常饲料喂养时，βOgtOE小鼠表现出正常的外周胰岛素敏感性和葡萄糖耐量。然而，当用高脂饮食进行刺激时，尽管胰岛素分泌增加且β细胞量正常，但只有雌性纯合（Hz）βOgtOE小鼠出现了轻度葡萄糖不耐受。虽然雌性小鼠通常对低剂量STZ处理具有抗性，但βOgtOE Hz小鼠在接受STZ处理后出现了高血糖和葡萄糖不耐受。通过RNA测序对Ogt缺失或过表达的胰岛进行转录组分析，结果显示，涉及促生存的细胞外信号调节激酶（Erk）和蛋白激酶B（Akt）以及炎症调节因子白细胞介素1β（IL1β）和核因子κB（NFκB）的信号通路发生了共同改变。综上所述，这些数据表明Ogt可能存在基因剂量效应，同时也表明O - GlcNAc循环在β细胞存活和功能以及调节葡萄糖稳态方面具有重要意义。
The nutrient-sensor O-GlcNAc transferase (Ogt), the sole enzyme that adds an O-GlcNAc-modification onto proteins, plays a critical role for pancreatic β-cell survival and insulin secretion. We hypothesized that β-cell Ogt overexpression would confer protection from β-cell failure in response to metabolic stressors, such as high-fat diet (HFD) and streptozocin (STZ). Here, we generated a β-cell-specific Ogt in overexpressing (βOgtOE) mice, where a significant increase in Ogt protein level and O-GlcNAc-modification of proteins were observed in islets under a normal chow diet. We uncovered that βOgtOE mice show normal peripheral insulin sensitivity and glucose tolerance with a regular chow diet. However, when challenged with an HFD, only female βOgtOE (homozygous) Hz mice developed a mild glucose intolerance, despite increased insulin secretion and normal β-cell mass. While female mice are normally resistant to low-dose STZ treatments, the βOgtOE Hz mice developed hyperglycemia and glucose intolerance post-STZ treatment. Transcriptome analysis between islets with loss or gain of Ogt by RNA sequencing shows common altered pathways involving pro-survival Erk and Akt and inflammatory regulators IL1β and NFkβ. Together, these data show a possible gene dosage effect of Ogt and the importance O-GlcNAc cycling in β-cell survival and function to regulate glucose homeostasis.
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影响因子：
8.8
作者：
Lockridge A;Jo S;Gustafson E;Damberg N;Mohan R;Olson M;Abrahante JE;Alejandro EU
通讯作者：
Alejandro EU
影响因子：
16.6
作者：
Yang, Yunfan;Fu, Minnie;Yang, Xiaoyong
通讯作者：
Yang, Xiaoyong
DOI：
10.1083/jcb.201501101
发表时间：
2015-03-30
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bond MR;Hanover JA
通讯作者：
Hanover JA
影响因子：
8.8
作者：
Alejandro EU;Bozadjieva N;Kumusoglu D;Abdulhamid S;Levine H;Haataja L;Vadrevu S;Satin LS;Arvan P;Bernal-Mizrachi E
通讯作者：
Bernal-Mizrachi E
影响因子：
15.9
作者：
Bernal-Mizrachi, E;Wen, W;Permutt, MA
通讯作者：
Permutt, MA