The Nuclear Orphan Receptor Nur77 Is a Lipotoxicity Sensor Regulating Glucose-Induced Insulin Secretion in Pancreatic β-Cells
The Nuclear Orphan Receptor Nur77 Is a Lipotoxicity Sensor Regulating Glucose-Induced Insulin Secretion in Pancreatic β-Cells
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DOI：
10.1210/me.2011-1317
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发表时间：
2012-03-01
影响因子：
--
通讯作者：
Lefebvre, Philippe
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文献类型：
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作者：
Briand, Olivier;Helleboid-Chapman, Audrey;Lefebvre, Philippe
NR4A孤儿核受体Nur77、Nurr1和Nor1发挥多种细胞和代谢功能。这些转录调节因子在响应细胞外应激时被激活，包括脂毒性脂肪酸（FA）和促炎细胞因子。然而，NR4As对β细胞病理生理的贡献尚不清楚。因此，我们研究了NR4As作为fa诱导的β细胞功能障碍的下游贡献者的作用。研究人员利用人胰岛和胰岛素瘤β细胞来确定NR4A引发的转录程序，并将其与棕榈酸盐治疗引发的转录程序进行比较。功能研究评估了NR4A表达增加对胰岛素瘤β细胞中胰岛素生物合成、分泌和细胞活力的影响。FA和细胞因子处理增加了胰腺β细胞中NR4A的表达，其中Nur77在小鼠β细胞中的诱导程度最高。Nur77、Nurr1或Nor1调节了与阳离子稳态和胰岛素基因转录相关的常见和独特的基因簇。通过改变锌稳态、胰岛素基因转录和分泌，Nur77被发现是部分fa诱导的β细胞功能障碍的主要转录介质。Nur77在胰岛素基因调控中的抑制作用可追溯到与fox01的蛋白-蛋白相互作用，fox01是胰岛素基因调控网络的关键整合子。本研究确定了NR4A核受体亚类Nur77/NR4A1的成员作为胰腺β细胞生物学的调节剂。再加上其先前在肝脏和肌肉中的作用，它在β细胞中的作用使Nur77成为葡萄糖代谢的重要整合体。（分子内分泌学26:399-413,2012）
The NR4A orphan nuclear receptors Nur77, Nurr1, and Nor1 exert multiple cellular and metabolic functions. These transcriptional regulators are activated in response to extracellular stresses, including lipotoxic fatty acids (FA) and proinflammatory cytokines. The contribution of NR4As to beta-cell pathophysiology is, however, unknown. We have therefore examined the role of NR4As as downstream contributors to FA-induced beta-cell dysfunctions. Human pancreatic islets and insulinoma beta-cells were used to determine transcriptional programs elicited by NR4A, which were compared to those triggered by palmitate treatment. Functional studies evaluated the consequence of an increased NR4A expression on insulin biosynthesis and secretion and cell viability in insulinoma beta-cells. FA and cytokine treatment increased NR4A expression in pancreatic beta-cells, with Nur77 being most highly inducible in murine beta-cells. Nur77, Nurr1, or Nor1 modulated common and distinct clusters of genes involved notably in cation homeostasis and insulin gene transcription. By altering zinc homeostasis, insulin gene transcription, and secretion, Nur77 was found to be a major transcriptional mediator of part of FA-induced beta-cell dysfunctions. The repressive role of Nur77 in insulin gene regulation was tracked down to protein-protein interaction with FoxO1, a pivotal integrator of the insulin gene regulatory network. The present study identifies a member of the NR4A nuclear receptor subclass, Nur77/NR4A1, as a modulator of pancreatic beta-cell biology. Together with its previously documented role in liver and muscle, its role in beta-cells establishes Nur77 as an important integrator of glucose metabolism. (Molecular Endocrinology 26: 399-413, 2012)