Arsenic Induces Insulin Resistance in Mouse Adipocytes and Myotubes Via Oxidative Stress-Regulated Mitochondrial Sirt3-FOXO3a Signaling Pathway
Arsenic Induces Insulin Resistance in Mouse Adipocytes and Myotubes Via Oxidative Stress-Regulated Mitochondrial Sirt3-FOXO3a Signaling Pathway
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DOI：
10.1093/toxsci/kfv089
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发表时间：
2015-08-01
影响因子：
3.8
通讯作者：
Zhang, Zhuo
中科院分区：
文献类型：
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作者：
Divya, Sasidharan Padmaja;Pratheeshkumar, Poyil;Zhang, Zhuo
通过饮用水长期暴露于砷与2型糖尿病（T2 DM）的风险增加有关。本研究探讨线粒体氧化应激蛋白Sirtuin 3（Sirt 3）及其靶蛋白在慢性砷诱导的小鼠脂肪细胞和肌管T2 DM中的作用。结果表明，慢性砷暴露显着降低胰岛素刺激的葡萄糖摄取（ISGU）与胰岛素调节的葡萄糖转运蛋白4型（Glut 4）的表达减少。砷暴露后，线粒体脱乙酰酶Sirt 3及其相关转录因子FOXO 3a的表达沿着显著降低。在砷处理的3 T3 L1脂肪细胞和C2 C12肌管中均观察到线粒体膜电位（Δ psi m）降低。砷降低FOXO 3a活性，表现出对锰超氧化物歧化酶（MnSOD）和过氧化物酶体增殖物激活受体-γ共激活因子（PGC）-1 α（一种广泛而强大的活性氧（ROS）代谢调节剂）启动子的结合亲和力降低。Sirt 3或MnSOD在小鼠肌管中的强制表达升高Δ psi m，并恢复砷暴露抑制的ISGU。我们的研究结果表明，Sirt 3/FOXO 3a/MnSOD信号通路在慢性砷暴露诱导的ISGU抑制中起着重要作用。
Chronic exposure to arsenic via drinking water is associated with an increased risk for development of type 2 diabetes mellitus (T2DM). This study investigates the role of mitochondrial oxidative stress protein Sirtuin 3 (Sirt3) and its targeting proteins in chronic arsenic-induced T2DM in mouse adipocytes and myotubes. The results show that chronic arsenic exposure significantly decreased insulin-stimulated glucose uptake (ISGU) in correlation with reduced expression of insulin-regulated glucose transporter type 4 (Glut4). Expression of Sirt3, a mitochondrial deacetylase, was dramatically decreased along with its associated transcription factor, forkhead box O3 (FOXO3a) upon arsenic exposure. A decrease in mitochondrial membrane potential (Delta psi m) was observed in both 3T3L1 adipocytes and C2C12 myotubes treated by arsenic. Reduced FOXO3a activity by arsenic exhibited a decreased binding affinity to the promoters of both manganese superoxide dismutase (MnSOD) and peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1 alpha, a broad and powerful regulator of reactive oxygen species (ROS) metabolism. Forced expression of Sirt3 or MnSOD in mouse myotubes elevated Delta psi m and restored ISGU inhibited by arsenic exposure. Our results suggest that Sirt3/FOXO3a/MnSOD signaling plays a significant role in the inhibition of ISGU induced by chronic arsenic exposure.