Coffey Richard, Nam Hyeyoung, Knutson Mitchell D
Food Science and Human Nutrition Department, University of Florida, Gainesville, Florida, United States of America.
PLoS One. 2014 Jan 21;9(1):e86019. doi: 10.1371/journal.pone.0086019. eCollection 2014.
It is well known that iron overload can result in pancreatic iron deposition, beta-cell destruction, and diabetes in humans. Recent studies in animals have extended the link between iron status and pancreatic function by showing that iron depletion confers protection against beta-cell dysfunction and diabetes. The aim of the present study was to identify genes in the pancreas that are differentially expressed in response to iron deficiency or overload. Weanling male Sprague-Dawley rats (n = 6/group) were fed iron-deficient, iron-adequate, or iron-overloaded diets for 3 weeks to alter their iron status. Total RNA was isolated from the pancreases and pooled within each group for microarray analyses in which gene expression levels were compared to those in iron-adequate controls. In iron-deficient pancreas, a total of 66 genes were found to be differentially regulated (10 up, 56 down), whereas in iron-overloaded pancreas, 164 genes were affected (82 up, 82 down). The most up-regulated transcript in iron-deficient pancreas was arachidonate 15-lipoxygenase (Alox15), which has been implicated in the development of diabetes. In iron-overloaded pancreas, the most upregulated transcripts were Reg1a, Reg3a, and Reg3b belonging to the regenerating islet-derived gene (Reg) family. Reg expression has been observed in response to pancreatic stress and is thought to facilitate pancreatic regeneration. Subsequent qRT-PCR validation indicated that Alox15 mRNA levels were 4 times higher in iron-deficient than in iron-adequate pancreas and that Reg1a, Reg3a, and Reg3b mRNA levels were 17-36 times higher in iron-overloaded pancreas. The elevated Alox15 mRNA levels in iron-deficient pancreas were associated with 8-fold higher levels of Alox15 protein as indicated by Western blotting. Overall, these data raise the possibility that Reg expression may serve as a biomarker for iron-related pancreatic stress, and that iron deficiency may adversely affect the risk of developing diabetes through up-regulation of Alox15.
众所周知，铁过载可导致人体胰腺铁沉积、β细胞破坏及糖尿病。近期动物研究通过表明铁耗竭可预防β细胞功能障碍和糖尿病，进一步拓展了铁状态与胰腺功能之间的联系。本研究的目的是鉴定胰腺中因缺铁或铁过载而差异表达的基因。将断乳雄性斯普拉格-道利大鼠（每组n = 6）喂食缺铁、铁充足或铁过载饮食3周以改变其铁状态。从胰腺中分离总RNA，并在每组内汇集用于微阵列分析，其中将基因表达水平与铁充足对照组进行比较。在缺铁胰腺中，共发现66个基因受到差异调节（10个上调，56个下调），而在铁过载胰腺中，164个基因受到影响（82个上调，82个下调）。缺铁胰腺中上调最明显的转录本是花生四烯酸15-脂氧合酶（Alox15），其与糖尿病的发生有关。在铁过载胰腺中，上调最明显的转录本是属于再生胰岛衍生基因（Reg）家族的Reg1a、Reg3a和Reg3b。已观察到Reg表达可响应胰腺应激，并被认为有助于胰腺再生。随后的qRT-PCR验证表明，缺铁胰腺中Alox15 mRNA水平比铁充足胰腺高4倍，而铁过载胰腺中Reg1a、Reg3a和Reg3b mRNA水平高17 - 36倍。蛋白质印迹显示，缺铁胰腺中升高的Alox15 mRNA水平与Alox15蛋白水平高8倍相关。总体而言，这些数据增加了以下可能性：Reg表达可能作为铁相关胰腺应激的生物标志物，并且缺铁可能通过上调Alox15对患糖尿病风险产生不利影响。
