Chronic ethanol consumption inhibits glucokinase transcriptional activity by Atf3 and triggers metabolic syndrome in vivo.
Chronic ethanol consumption inhibits glucokinase transcriptional activity by Atf3 and triggers metabolic syndrome in vivo.
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DOI：
10.1074/jbc.m114.585653
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发表时间：
2014-09-26
期刊：
影响因子：
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通讯作者：
Kim WH
中科院分区：
文献类型：
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作者：
Kim JY;Hwang JY;Lee DY;Song EH;Park KJ;Kim GH;Jeong EA;Lee YJ;Go MJ;Kim DJ;Lee SS;Kim BJ;Song J;Roh GS;Gao B;Kim WH
背景：慢性酒精摄入可导致胰腺β细胞功能障碍和代谢综合征。结果：乙醇诱导的ATF3通过直接结合或通过ATF3/PDX-1/HDAC1轴与葡萄糖激酶启动子结合而抑制其转录活性。结论：ATF3通过下调GCK而促进β细胞功能障碍，并触发T2D，体内沉默ATF3可改善这种功能。意义：目前的数据揭示了ATF3作为治疗2型糖尿病的潜在治疗靶点的新作用。慢性酒精摄入通过葡萄糖激酶硝化和下调诱导胰腺β细胞功能障碍，导致糖耐量受损和胰岛素抵抗，但其潜在机制尚不清楚。在此，我们证明了在体内和体外，慢性乙醇暴露抑制了胰腺β-细胞中GCK基因的表达和启动子的活性，而激活转录因子3(ATF3)的表达及其与GCK启动子上假定的ATF/CREB位点(−287至−158bp)的结合被上调。此外，在体外乙醇诱导的ATF3抑制了PDX-1对GCK转录调控的正向作用，增强了HDAC1/2和组蛋白H3去乙酰化的募集，进而增强了HDAC1/PDX-1与GCK启动子的相互作用，而ATF3 siRNA减弱了这种作用。在体内，ATF3沉默逆转了乙醇介导的GCK下调和β细胞功能障碍，继而改善了糖耐量受损和胰岛素抵抗。我们共同确认，乙醇诱导的ATF3通过GCK下调促进β细胞功能障碍，其缺失可以改善代谢综合征，并可能成为治疗2型糖尿病的潜在治疗靶点。ATF3基因与2型糖尿病的诱发和饮酒引起的代谢损伤有关，因此可能是葡萄糖稳态的主要负调节因子。
Background: Chronic ethanol consumption induces pancreatic β-cell dysfunction and metabolic syndrome. Results: Ethanol-induced Atf3 inhibits glucokinase transcriptional activity through direct binding or Atf3/Pdx-1/Hdac1 axis on glucokinase promoter. Conclusion: ATf3 fosters β-cell dysfunction via Gck down-regulation and triggers T2D, which is ameliorated by in vivo Atf3 silencing. Significance: The presented data uncover a new role for Atf3 as a potential therapeutic target in treating type 2 diabetes. Chronic ethanol consumption induces pancreatic β-cell dysfunction through glucokinase (Gck) nitration and down-regulation, leading to impaired glucose tolerance and insulin resistance, but the underlying mechanism remains largely unknown. Here, we demonstrate that Gck gene expression and promoter activity in pancreatic β-cells were suppressed by chronic ethanol exposure in vivo and in vitro, whereas expression of activating transcription factor 3 (Atf3) and its binding to the putative Atf/Creb site (from −287 to −158 bp) on the Gck promoter were up-regulated. Furthermore, in vitro ethanol-induced Atf3 inhibited the positive effect of Pdx-1 on Gck transcriptional regulation, enhanced recruitment of Hdac1/2 and histone H3 deacetylation, and subsequently augmented the interaction of Hdac1/Pdx-1 on the Gck promoter, which were diminished by Atf3 siRNA. In vivo Atf3-silencing reversed ethanol-mediated Gck down-regulation and β-cell dysfunction, followed by the amelioration of impaired glucose tolerance and insulin resistance. Together, we identified that ethanol-induced Atf3 fosters β-cell dysfunction via Gck down-regulation and that its loss ameliorates metabolic syndrome and could be a potential therapeutic target in treating type 2 diabetes. The Atf3 gene is associated with the induction of type 2 diabetes and alcohol consumption-induced metabolic impairment and thus may be the major negative regulator for glucose homeostasis.