Lawson Rebecca, Maret Wolfgang, Hogstrand Christer
King's College London, Faculty of Life Sciences and Medicine, Diabetes and Nutritional Sciences, Metal Metabolism Group, 150 Stamford St, London, SE1 9NH, UK.
BMC Genomics. 2017 Sep 11;18(1):719. doi: 10.1186/s12864-017-4119-2.
Pancreatic β-cells require a constant supply of zinc to maintain normal insulin secretory function. Following co-exocytosis with insulin, zinc is replenished via the Zrt- and Irt-like (ZIP; SLC39A) family of transporters. However the ZIP paralogues of particular importance for zinc uptake, and associations with β-cell function and Type 2 Diabetes remain largely unexplored. We retrieved and statistically analysed publically available microarray and RNA-seq datasets to perform a systematic review on the expression of β-cell SLC39A paralogues. We complemented results with experimental data on expression profiling of human islets and mouse β-cell derived MIN6 cells, and compared transcriptomic and proteomic sequence conservation between human, mouse and rat.
The 14 ZIP paralogues have 73-98% amino sequence conservation between human and rodents. We identified 18 datasets for β-cell SLC39A analysis, which compared relative expression to non-β-cells, and expression in response to PDX-1 activity, cytokines, glucose and type 2 diabetic status. Published expression data demonstrate enrichment of transcripts for ZIP7 and ZIP9 transporters within rodent β-cells and of ZIP6, ZIP7 and ZIP14 within human β-cells, with ZIP1 most differentially expressed in response to cytokines and PDX-1 within rodent, and ZIP6 in response to diabetic status in human and glucose in rat. Our qPCR expression profiling data indicate that SLC39A6, -9, -13, and - 14 are the highest expressed paralogues in human β-cells and Slc39a6 and -7 in MIN6 cells.
Our systematic review, expression profiling and sequence alignment reveal similarities and potentially important differences in ZIP complements between human and rodent β-cells. We identify ZIP6, ZIP7, ZIP9, ZIP13 and ZIP14 in human and rodent and ZIP1 in rodent as potentially biologically important for β-cell zinc trafficking. We propose ZIP6 and ZIP7 are key functional orthologues in human and rodent β-cells and highlight these zinc importers as important targets for exploring associations between zinc status and normal physiology of β-cells and their decline in Type 2 Diabetes.
胰腺β细胞需要持续供应锌以维持正常的胰岛素分泌功能。与胰岛素共同胞吐后，锌通过锌转运体相关蛋白（Zrt）和铁转运体相关蛋白（Irt）样（ZIP；溶质载体家族39成员A，SLC39A）转运体家族进行补充。然而，对于锌摄取特别重要的ZIP同源物以及与β细胞功能和2型糖尿病的关联在很大程度上仍未得到探索。我们检索并统计分析了公开可用的微阵列和RNA测序数据集，以对β细胞SLC39A同源物的表达进行系统综述。我们用人胰岛和小鼠β细胞来源的MIN6细胞的表达谱实验数据补充结果，并比较了人、小鼠和大鼠之间的转录组和蛋白质组序列保守性。
14种ZIP同源物在人和啮齿动物之间具有73% - 98%的氨基酸序列保守性。我们确定了18个用于β细胞SLC39A分析的数据集，这些数据集比较了与非β细胞的相对表达，以及对胰腺十二指肠同源盒1（PDX - 1）活性、细胞因子、葡萄糖和2型糖尿病状态的反应中的表达。已发表的表达数据表明，啮齿动物β细胞中ZIP7和ZIP9转运体的转录本富集，人β细胞中ZIP6、ZIP7和ZIP14富集，啮齿动物中ZIP1在对细胞因子和PDX - 1的反应中差异表达最大，人β细胞中ZIP6在对糖尿病状态的反应中差异表达最大，大鼠β细胞中ZIP6在对葡萄糖的反应中差异表达最大。我们的定量聚合酶链反应（qPCR）表达谱数据表明，SLC39A6、 - 9、 - 13和 - 14是人β细胞中表达最高的同源物，Slc39a6和 - 7是MIN6细胞中表达最高的同源物。
我们的系统综述、表达谱分析和序列比对揭示了人和啮齿动物β细胞中ZIP补充物的相似性和潜在的重要差异。我们确定人及啮齿动物中的ZIP6、ZIP7、ZIP9、ZIP13和ZIP14以及啮齿动物中的ZIP1对β细胞锌转运可能具有生物学重要性。我们提出ZIP6和ZIP7是人及啮齿动物β细胞中的关键功能直系同源物，并强调这些锌导入蛋白是探索锌状态与β细胞正常生理及其在2型糖尿病中功能衰退之间关联的重要靶点。
