Transcription factor Ets-1 links glucotoxicity to pancreatic beta cell dysfunction through inhibiting PDX-1 expression in rodent models
Transcription factor Ets-1 links glucotoxicity to pancreatic beta cell dysfunction through inhibiting PDX-1 expression in rodent models
复制标题
转录因子 Ets-1 通过抑制啮齿动物模型中的 PDX-1 表达，将糖毒性与胰腺 β 细胞功能障碍联系起来
DOI：
10.1007/s00125-015-3805-3
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发表时间：
2016-02-01
期刊：
影响因子：
8.2
通讯作者：
Han, Xiao
中科院分区：
文献类型：
--
作者：
Chen, Fang;Sha, Min;Han, Xiao
目的/假说‘葡萄糖毒性’是一个用来表达高血糖对β细胞功能的负面影响的术语；然而，损害胰岛素分泌和基因表达的潜在分子机制尚不清楚。本研究的目的是探讨转录因子v-ETS禽红母细胞增殖症病毒E26癌基因同源物1(ETS-1)在β细胞糖毒中的作用。方法将原代胰岛和Min6细胞暴露于高糖环境中，检测ETS-1的表达。用重组腺病毒和转基因小鼠在体内外上调Ets-1在β细胞中的表达，并测定胰岛素的分泌。结果高糖诱导β细胞Ets-1基因启动子Ets-1表达上调和组蛋白H3、H4高乙酰化。Ets-1过表达显著抑制体内和体外胰岛素的分泌和生物合成。此外，Ets-1过表达增加了FOXO1的活性，但降低了FOXA2与胰腺和十二指肠同源盒1(PDX-1)同源区2(PH2)的结合活性，从而抑制了PDX-1的启动子活性，下调了PDX-1的表达和活性。此外，高糖还促进了ETS-1与FOXO1的相互作用以及ETS-1与PDX-1启动子结合的活性。重要的是，PDX-1的过表达逆转了由ETS-1过量导致的胰岛β细胞缺陷，而ETS-1的敲除则阻止了高血糖诱导的胰岛β细胞功能障碍。结论我们的观察表明，在2型糖尿病中，ETS-1通过抑制PDX-1的表达而将糖毒性与胰岛β细胞功能障碍联系起来。
Aims/hypothesis 'Glucotoxicity' is a term used to convey the negative effect of hyperglycaemia on beta cell function; however, the underlying molecular mechanisms that impair insulin secretion and gene expression are poorly defined. Our objective was to define the role of transcription factor v-ets avian erythroblastosis virus E26 oncogene homologue 1 (Ets-1) in beta cell glucotoxicity.Methods Primary islets and Min6 cells were exposed to high glucose and Ets-1 expression was measured. Recombinant adenovirus and transgenic mice were used to upregulate Ets-1 expression in beta cells in vitro and in vivo, and insulin secretion was assessed. The binding activity of H3/H4 histone on the Ets-1 promoter, and that of forkhead box (FOX)A2, FOXO1 and Ets-1 on the Pdx-1 promoter was measured by chromatin immunoprecipitation and quantitative real-time PCR assay.Results High glucose induced upregulation of Ets-1 expression and hyperacetylation of histone H3 and H4 at the Ets-1 gene promoter in beta cells. Ets-1 overexpression dramatically suppressed insulin secretion and biosynthesis both in vivo and in vitro. Besides, Ets-1 overexpression increased the activity of FOXO1 but decreased that of FOXA2 binding to the pancreatic and duodenal homeobox 1 (PDX-1) homology region 2 (PH2), resulting in inhibition of Pdx-1 promoter activity and downregulation of PDX-1 expression and activity. In addition, high glucose promoted the interaction of Ets-1 and FOXO1, and the activity of Ets-1 binding to the Pdx-1 promoter. Importantly, PDX-1 overexpression reversed the defect in pancreatic beta cells induced by Ets-1 excess, while knockdown of Ets-1 prevented hyperglycaemia-induced dysfunction of pancreatic beta cells.Conclusions/interpretation Our observations suggest that Ets-1 links glucotoxicity to pancreatic beta cell dysfunction through inhibiting PDX-1 expression in type 2 diabetes.