Nutritional Genomics Laboratory, Food Science and Human Nutrition Department, Center for Nutritional Sciences, University of Florida, Gainesville, FL 32611-0370, USA.
Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):2818-23. doi: 10.1073/pnas.0914941107. Epub 2010 Jan 27.
The exocrine pancreas plays an important role in endogenous zinc loss by regulating excretion into the intestinal tract and hence influences the dietary zinc requirement. The present experiments show that the zinc transporter ZnT2 (Slc30a2) is localized to the zymogen granules and that dietary zinc restriction in mice decreased the zinc concentration of zymogen granules and ZnT2 expression. Excess zinc given orally increased ZnT2 expression and was associated with increased pancreatic zinc accumulation. Rat AR42J acinar cells when induced into a secretory phenotype, using the glucocorticoid analog dexamethasone (DEX), exhibited increased ZnT2 expression and labile zinc as measured with a fluorophore. DEX administrated to mice also induced ZnT2 expression that accompanied a reduction of the pancreatic zinc content. ZnT2 promoter analyses identified elements required for responsiveness to zinc and DEX. Zinc regulation was traced to a MRE located downstream from the ZnT2 transcription start site. Responsiveness to DEX is produced by two upstream STAT5 binding sites that require the glucocorticoid receptor for activation. ZnT2 knockdown in the AR42J cells using siRNA resulted in increased cytoplasmic zinc and decreased zymogen granule zinc that further demonstrated that ZnT2 may mediate the sequestration of zinc into zymogen granules. We conclude, based upon experiments with intact mice and pancreatic acinar cells in culture, that ZnT2 participates in zinc transport into pancreatic zymogen granules through a glucocorticoid pathway requiring glucocorticoid receptor and STAT5, and zinc-regulated signaling pathways requiring MTF-1. The ZnT2 transporter appears to function in a physiologically responsive manner involving entero-pancreatic zinc trafficking.
外分泌胰腺通过调节肠道排泄在体内锌丢失中起着重要作用，因此影响膳食锌的需要量。本实验表明，锌转运蛋白 ZnT2（Slc30a2）定位于酶原颗粒，并且饮食锌限制降低了酶原颗粒的锌浓度和 ZnT2 表达。口服给予过量的锌会增加 ZnT2 的表达，并与胰腺锌积累增加有关。当使用糖皮质激素类似物地塞米松（DEX）将大鼠 AR42J 腺泡细胞诱导成分泌表型时，观察到 ZnT2 表达增加和不稳定锌（用荧光团测量）。DEX 给予小鼠也诱导了 ZnT2 表达，同时降低了胰腺中的锌含量。ZnT2 启动子分析鉴定了对锌和 DEX 反应所必需的元件。锌的调节可追溯到 ZnT2 转录起始位点下游的 MRE。DEX 的反应性是由两个上游 STAT5 结合位点产生的，这些位点需要糖皮质激素受体才能激活。用 siRNA 在 AR42J 细胞中敲低 ZnT2 会导致细胞质锌增加和酶原颗粒锌减少，这进一步表明 ZnT2 可能介导锌向酶原颗粒的隔离。我们的结论是，基于完整小鼠和培养的胰腺腺泡细胞的实验，ZnT2 通过需要糖皮质激素受体和 STAT5 的糖皮质激素途径参与锌向胰腺酶原颗粒的转运，并且需要 MTF-1 的锌调节信号通路。ZnT2 转运蛋白似乎以涉及肠胰锌转运的生理反应方式发挥作用。
