Mitochondrial Dysfunction and Increased Reactive Oxygen Species Impair Insulin Secretion in Sphingomyelin Synthase 1-null Mice
Mitochondrial Dysfunction and Increased Reactive Oxygen Species Impair Insulin Secretion in Sphingomyelin Synthase 1-null Mice
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DOI：
10.1074/jbc.m110.179176
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发表时间：
2011-02-04
影响因子：
4.8
通讯作者：
Oike, Yuichi
中科院分区：
文献类型：
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作者：
Yano, Masato;Watanabe, Ken;Oike, Yuichi
鞘磷脂合成酶1(SMS1)催化神经酰胺转化为鞘磷脂。在这里，我们产生并分析了SMS1缺失的小鼠。SMS1基因缺失的小鼠表现出中等的新生儿死亡率，体重减轻，脂肪组织质量减少，这表明它们可能存在代谢异常。事实上，对葡萄糖代谢的分析显示，他们的胰岛素分泌严重不足。分离的突变胰岛表现出严重的胰岛素释放能力受损，依赖于葡萄糖刺激。进一步的分析表明，突变的胰岛细胞中的线粒体不能上调ATP的产生以响应葡萄糖。我们还观察到了额外的线粒体异常，如超极化的膜电位和突变胰岛中活性氧物种(ROS)水平的增加。最后，当SMS1基因缺失的小鼠接受抗氧化剂N-乙酰半胱氨酸治疗时，我们观察到胰岛素分泌的部分恢复，表明ROS的过度产生是SMS1基因缺失小鼠胰岛β细胞功能障碍的基础。总之，我们的数据表明，SMS1对于控制ROS的产生是重要的，并且SMS1对于正常的线粒体功能和胰岛β细胞的胰岛素分泌是必需的。
Sphingomyelin synthase 1 (SMS1) catalyzes the conversion of ceramide to sphingomyelin. Here, we generated and analyzed SMS1-null mice. SMS1-null mice exhibited moderate neonatal lethality, reduced body weight, and loss of fat tissues mass, suggesting that they might have metabolic abnormality. Indeed, analysis on glucose metabolism revealed that they showed severe deficiencies in insulin secretion. Isolated mutant islets exhibited severely impaired ability to release insulin, dependent on glucose stimuli. Further analysis indicated that mitochondria in mutant islet cells cannot up-regulate ATP production in response to glucose. We also observed additional mitochondrial abnormalities, such as hyperpolarized membrane potential and increased levels of reactive oxygen species (ROS) in mutant islets. Finally, when SMS1-null mice were treated with the anti-oxidant N-acetyl cysteine, we observed partial recovery of insulin secretion, indicating that ROS overproduction underlies pancreatic beta-cell dysfunction in SMS1-null mice. Altogether, our data suggest that SMS1 is important for controlling ROS generation, and that SMS1 is required for normal mitochondrial function and insulin secretion in pancreatic beta-cells.