核受体NR4A1保护β细胞免受内质网应激诱发的细胞凋亡

摘要 : 七月八日，山东大学医学院关键岗教授王向东带领的一项研究，刊登在国际著名学术期刊《Journal of Biological Chemistry》。这项研究表明，核受体NR4A1可通过上调Survivin和下调CHOP的表达，保护β细胞免受内质网应激诱发的细胞凋亡，从而为糖尿病的预防提供了线索。

核受体NR4A1在细胞凋亡中的作用是有争议的。胰腺β细胞在不利条件下常常面临内质网(ER)应激，如高浓度的游离脂肪酸(FFA)和持续的高血糖。严重内质网应激可导致细胞凋亡。这项研究的目的在于，分析NR4A1在内质网应激介导的β细胞凋亡中的作用，并表征相关机制。

该研究小组确定，用ER应激诱导剂毒胡萝卜素(TG)或软脂酸(PA)处理后，MIN6细胞和小鼠胰岛中的mRNA和NR4A1水平迅速增加。通过MTT法和TUNEL检测表明，NR4A1表达也可防止内质网应激诱导的细胞凋亡。通过实验，利用sirna敲除MIN6细胞中的NR4A1表达或利用基因敲除小鼠，可进一步证实这个结论。

NR4A1在MIN6细胞中的过度表达，会降低C/EBP同源蛋白(CHOP)的表达，和TG或PAA诱导的Caspase3活化。NR4A1在MIN6细胞或小鼠胰岛中的过度表达，可导致Survivin上调。研究人员在具有一个假定NR4A1结合位点的Survivin启动子区(-1872 bp to -1866 bp)，发现了一个关键的调控元件;chip分析表明，NR4A1与Survivin启动子之间可发生相互作用。

总之，这些结果表明，NR4A1可通过上调Survivin的表达和下调CHOP的表达(我们称之为“正、负调控”)，保护胰腺β细胞免于内质网应激介导的细胞凋亡。

原文标题：The Orphan Nuclear Receptor NR4A1 Protects Pancreatic β-Cells from ER-Stress-Mediated Apoptosis

原文摘要：Abstract: The role of NR4A1 in apoptosis is controversial. Pancreatic β-cells often face ER-stress under adverse conditions such as high free fatty acid (FFA) concentrations and sustained hyperglycaemia. Severe ER-stress results in β-cell apoptosis. The aim of this study was to analyze the role of NR4A1 in ER-stress-mediated β-cell apoptosis and to characterize the related mechanisms. We confirmed that upon treatment with the ER stress inducers thapsigargin (TG) or palmitic acid (PA), the mRNA and protein levels of NR4A1 rapidly increased in both MIN6 cells and mouse islets. NR4A1 over-expression in MIN6 cells conferred resistance to cell loss induced by TG or PA, as assessed by MTT assay, and TUNEL assays indicated that NR4A1 over-expression also protected against ER stress-induced apoptosis. This conclusion was further confirmed by experiments exploiting siRNA to knockdown NR4A1 expression in MIN6 cells or exploiting NR4A1 knockout mice. NR4A1 over-expression in MIN6 cells reduced C/EBP homologous protein (CHOP) expression and Caspase3 activation induced by TG or PA. NR4A1 over-expression in MIN6 cells or mouse islets resulted in Survivin up-regulation. A critical regulatory element was identified in Survivin promoter (-1872 bp to -1866 bp) with a putative NR4A1 binding site; ChIP assays demonstrated that NR4A1 physically associates with the Survivin promoter. In conclusion, NR4A1 protects pancreatic β-cells against ER-stress-mediated apoptosis by up-regulating Survivin expression and down-regulating CHOP expression, which we termed as "positive and negative regulation".

作者：秩名

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