Activation of Akt through 5-HT2A receptor ameliorates serotonin-induced degradation of insulin receptor substrate-1 in adipocytes
Activation of Akt through 5-HT2A receptor ameliorates serotonin-induced degradation of insulin receptor substrate-1 in adipocytes
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DOI：
10.1016/j.mce.2012.08.022
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发表时间：
2013-01-05
影响因子：
4.1
通讯作者：
Funaki, Makoto
中科院分区：
文献类型：
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作者：
Li, Qinkai;Hosaka, Toshio;Funaki, Makoto
发现糖尿病患者血清中5-羟色胺（5-HT）升高。本研究旨在探讨5-HT对胰岛素减敏作用的机制。在3 T3-L1脂肪细胞中，5-HT处理诱导胰岛素受体底物-1（IRS-1）从低密度微粒体（LDM）（其功能的重要细胞内隔室）易位到胞质溶胶，诱导IRS-1泛素化和降解。此外，通过酮色林（一种特异性5-HT 2A受体拮抗剂）或敲低5-HT 2A受体的表达抑制5-HT刺激的Akt活化促进5-HT刺激的IRS-1从LDM中的14-3-3 β解离，导致剧烈的泛素化。有趣的是，另一种5-HT 2A受体拮抗剂沙格雷酯通过激活Akt保护IRS-1免于降解。这暗示了Akt活化在通过维持IRS-1在脂肪细胞中的最佳亚位置来延长IRS-1寿命中的重要性。综上所述，本研究表明，Akt的激活可能能够通过稳定IRS-1在LDM中补偿5-HT的不利影响。(C)2012爱思唯尔爱尔兰有限公司保留所有权利。
Serotonin (5-hydroxytryptamine, 5-HT) was found to be elevated in the serum of diabetic patients. In this study, we investigate the mechanism of insulin desensitization caused by 5-HT. In 3T3-L1 adipocytes, 5-HT treatment induced the translocation of insulin receptor substrate-1 (IRS-1) from low density microsome (LDM), the important intracellular compartment for its functions, to cytosol, inducing IRS-1 ubiquitination and degradation. Moreover, inhibition of 5-HT-stimulated Akt activation by either ketanserin (a specific 5-HT2A receptor antagonist) or knocking-down the expression of 5-HT2A receptor promoted 5-HT-stimulated IRS-1 dissociation from 14-3-3 beta in LDM, leading to drastic ubiquitination. Interestingly, sarpogrelate, another antagonist of 5-HT2A receptor, protected IRS-1 from degradation through activation of Akt. This implicates the importance of Akt activation in extending IRS-1 life span through maintaining their optimal sub-location into adipocytes. Taken together, this study suggest that activation of Akt may be able to compensate the adverse effects of 5-HT by stabilizing IRS-1 in LDM. (C) 2012 Elsevier Ireland Ltd. All rights reserved.