Mitochondrial Dysfunction and Increased Reactive Oxygen Species Impair Insulin Secretion in Sphingomyelin Synthase 1-null Mice

作者：Yano Masato^*; Watanabe Ken; Yamamoto Tadashi; Ikeda Kazutaka; Senokuchi Takafumi; Lu Meihong; Kadomatsu Tsuyoshi; Tsukano Hiroto; Ikawa Masahito; Okabe Masaru; Yamaoka Shohei; Okazaki Toshiro; Umehara Hisanori; Gotoh Tomomi; Song Wen Jie; Node Koichi; Taguchi Ryo; Yamagata Kazuya; Oike Yuichi

来源：Journal of Biological Chemistry, 2011, 286(5): 3992-4002.

DOI：10.1074/jbc.M110.179176

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.

• 出版日期2011-2-4