Influence of Tyrphostin AG490 on the expression of diabetes-associated markers in human adipocytes.
Influence of Tyrphostin AG490 on the expression of diabetes-associated markers in human adipocytes.
复制标题
Tyrphostin AG490 对人类脂肪细胞中糖尿病相关标志物表达的影响。
DOI：
10.1007/s00251-012-0659-4
复制
发表时间：
2013
期刊：
影响因子：
3.2
通讯作者：
Atkinson,M
中科院分区：
文献类型：
--
作者：
Davoodi-Semiromi,Abdoreza;Wasserfall,CH;Hassanzadeh,A;Cooper-DeHoff,RM;Wabitsch,M;Atkinson,M
酪氨酸激酶抑制剂（TKi）有望治疗多种疾病，从肿瘤疾病到免疫介导的疾病。Tyrphostin AG490是一种有效的Jak-Stat TKi，可有效预防同种异体移植排斥反应、实验性自身免疫性疾病以及治疗癌症。然而，鉴于其调节这一重要但多效性的细胞内通路的能力，我们认为研究其对葡萄糖代谢以及与胰岛素不敏感和糖尿病相关的主要转录因子和脂肪因子表达的影响是很重要的。我们研究了AG490对体内葡萄糖水平的代谢影响，采用糖尿病动物模型，非肥胖糖尿病（NOD）小鼠，并通过评估人类脂肪细胞的转录因子表达。AG490治疗的年轻非糖尿病NOD小鼠显著降低血糖水平（p= 0.002）。罗格列酮是一种胰岛素增敏剂，可与过氧化物酶体增殖激活受体（PPAR）受体结合，增加脂肪细胞对胰岛素的反应。在体外，罗格列酮治疗脂肪细胞可显著增加抗糖尿病脂肪因子脂联素的表达。重要的是，罗格列酮联合Tyrphostin AG490进一步增强了这种作用，并与C增强结合蛋白（C/EBP）的显著上调特异性相关（p< 0.0001）。就这一作用的机制而言，ppar γ、ADIPOQ和c / ebp3的调控区域含有Stat5 dna结合序列，并通过体外凝胶转移实验得到了证实。这些数据表明，用AG490阻断Jak-Stat信号传导可降低血糖水平，并调节先前与糖尿病相关的转录因子的表达，从而支持其作为糖尿病治疗的潜力。
Tyrosine kinase inhibitors (TKi) hold promise as a treatment for a variety of disorders ranging from those in oncology to diseases thought as immune mediated. Tyrphostin AG490 is a potent Jak-Stat TKi shown effective in the prevention of allograft transplant rejection, experimental autoimmune disease, as well as the treatment of cancer. However, given its ability to modulate this important but pleiotropic intracellular pathway, we thought that it is important to examine its effects on glucose metabolism and expression of major transcription factors and adipokines associated with insulin insensitivity and diabetes. We investigated the metabolic effects of AG490 on glucose levels in vivo using an animal model of diabetes, nonobese diabetic (NOD) mice, and transcription factor expression through assessment of human adipocytes. AG490 treatment of young nondiabetic NOD mice significantly reduced blood glucose levels (p= 0.002). In vitro, treatment of adipocytes with rosiglitazone, an insulin sensitizer that binds to peroxisome proliferator-activated receptor (PPAR) receptors and increases the adipocyte response to insulin, significantly increased the expression of the antidiabetic adipokine adiponectin. Importantly, the combination of rosiglitazone plus Tyrphostin AG490 further increased this effect and was specifically associated with significant upregulation of C-enhanced binding protein (C/EBP) (p< 0.0001). In terms of the mechanism underlying this action, regulatory regions of thePPARγ,ADIPOQ, andC/EBPcontain the Stat5 DNA-binding sequences and were demonstrated, by gel shift experiments in vitro. These data suggest that blocking Jak-Stat signaling with AG490 reduces blood glucose levels and modulates the expression of transcription factors previously associated with diabetes, thereby supporting its potential as a therapy for this disease.