Dual-specificity tyrosine phosphorylation-regulated kinase 1A ameliorates insulin resistance in neurons by up-regulating IRS-1 expression
Dual-specificity tyrosine phosphorylation-regulated kinase 1A ameliorates insulin resistance in neurons by up-regulating IRS-1 expression
复制标题
双特异性酪氨酸磷酸化调节激酶 1A 通过上调 IRS-1 表达改善神经元胰岛素抵抗
DOI：
10.1074/jbc.ra119.010809
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发表时间：
2019
影响因子：
4.8
通讯作者：
Sun Xiulian
中科院分区：
文献类型：
--
作者：
Tian Shijiao;Jia Wenming;Lu Mei;Zhao Juan;Sun Xiulian
脑中的胰岛素抵抗是阿尔茨海默病（AD）和2型糖尿病（T2 DM）共有的病理机制。胰岛素受体底物1（IRS-1）的异常表达和磷酸化是胰岛素抵抗的重要机制。在本研究中，我们使用了多种方法，包括腺相关病毒蛋白过表达，免疫印迹，免疫沉淀，免疫组织化学和原位近端连接分析，研究双特异性酪氨酸磷酸化调节激酶1A（DYRK 1A）在IRS-1调节和下游胰岛素信号转导中的功能。我们发现DYRK 1A过表达通过减慢IRS-1蛋白的周转来上调IRS-1的表达。我们进一步观察到DYRK 1A与IRS-1直接相互作用并磷酸化IRS-1的多个丝氨酸残基。值得注意的是，DYRK 1A和IRS-1在db/db小鼠大脑的前额叶皮层中协同上调。此外，DYRK 1A过表达改善SH-SY 5 Y细胞以及原代大鼠神经元中慢性高胰岛素诱导的胰岛素抵抗。这些发现表明，DYRK 1A通过提高IRS-1表达来保护大脑免受胰岛素抵抗。
Insulin resistance in the brain is a pathological mechanism that is shared between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). Although aberrant expression and phosphorylation of insulin receptor substrate 1 (IRS-1) contribute to insulin resistance, the underlying mechanism remains elusive. In this study, we used several approaches, including adeno-associated virus-based protein overexpression, immunoblotting, immunoprecipitation, immunohistochemistry, andin situproximal ligation assays, to investigate the function of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) in IRS-1 regulation and the downstream insulin signaling in neurons. We found that DYRK1A overexpression up-regulated IRS-1 expression by slowing turnover of the IRS-1 protein. We further observed that DYRK1A directly interacted with IRS-1 and phosphorylated IRS-1's multiple serine residues. Of note, DYRK1A and IRS-1 were coordinately up-regulated in the prefrontal cortex ofdb/dbmice brain. Furthermore, DYRK1A overexpression ameliorated chronic high insulin-induced insulin resistance in SH-SY5Y cells as well as in primary rat neurons. These findings suggest that DYRK1A protects against insulin resistance in the brain by elevating IRS-1 expression.