Acute cytokine-mediated downregulation of the zinc transporter ZnT8 alters pancreatic beta-cell function.
Acute cytokine-mediated downregulation of the zinc transporter ZnT8 alters pancreatic beta-cell function.
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DOI：
10.1677/joe-09-0420
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发表时间：
2010-08
期刊：
影响因子：
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通讯作者：
Lowe WL Jr
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文献类型：
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作者：
El Muayed M;Billings LK;Raja MR;Zhang X;Park PJ;Newman MV;Kaufman DB;O'Halloran TV;Lowe WL Jr
遗传学研究表明，锌转运体如ZnT8在胰腺β-细胞分泌胰岛素中发挥作用；然而，锌转运途径在β细胞生理中的动态作用尚不清楚。为了研究炎性细胞因子白细胞介素1β (il - 1β)和肿瘤坏死因子α (TNFα)对锌稳态的急性影响，我们检测了ZnT和ZIP家族锌转运蛋白的mRNA表达谱。暴露于MIN6细胞或小鼠原代胰岛的il - 1β或tnf - α改变了Zn转运体的mRNA表达谱；最显著的是ZnT8 mRNA水平降低。通过sirna介导的基因敲低，研究了C57/BL6小鼠和MIN6细胞原代分散鼠胰岛细胞中ZnT8表达降低的影响。在正常或超生理锌浓度下，这些小鼠胰岛中ZnT8敲低导致葡萄糖刺激的胰岛素分泌减少，而不改变细胞总胰岛素含量或细胞活力。通过流式细胞术检测，负载了锌特异性传感器FluoZin-3 AM后，MIN6细胞中ZnT8敲除或il - 1β处理后，不稳定锌含量降低。这些结果表明，ZnT8水平的急性降低会损害β细胞功能和Zn稳态，并可能导致炎症细胞因子诱导的β细胞功能改变。
Genetic studies suggest that Zn transporters such as ZnT8 play a role in insulin secretion by pancreatic β-cells; however, little is known about the dynamic roles of Zn trafficking pathways on β-cell physiology. To test the acute effects of the inflammatory cytokines interleukin 1β (IL1β) and tumor necrosis factor α (TNFα) on Zn homeostasis, the mRNA expression profile of Zn transporters of the ZnT and ZIP families was examined. Exposure of MIN6 cells or primary murine islets to IL1β or TNFα altered the mRNA expression profile of Zn transporters; most notable was decreased ZnT8 mRNA levels. siRNA-mediated gene knockdown was used to examine the effects of decreased ZnT8 expression in primary dispersed murine islet cells from C57/BL6 mice and MIN6 cells. ZnT8 knockdown in these murine islets led to reduced glucose stimulated insulin secretion without altering the total cellular insulin content or cell viability at normal or supraphysiological Zn concentrations. The labile Zn content determined by flow cytometry after loading with the Zn-specific sensor FluoZin-3 AM was decreased in MIN6 cells following ZnT8 knockdown or IL1β treatment. These results suggest that an acute decrease in ZnT8 levels impairs β-cell function and Zn homeostasis, and may contribute to inflammatory cytokine-induced alterations in β-cell function.