Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, 44106, USA.
Sci Rep. 2018 Apr 26;8(1):6556. doi: 10.1038/s41598-018-24786-1.
The prion protein (PrP), a mainly neuronal protein, is known to modulate glucose homeostasis in mouse models. We explored the underlying mechanism in mouse models and the human pancreatic β-cell line 1.1B4. We report expression of PrP on mouse pancreatic β-cells, where it promoted uptake of iron through divalent-metal-transporters. Accordingly, pancreatic iron stores in PrP knockout mice (PrP) were significantly lower than wild type (PrP) controls. Silencing of PrP in 1.1B4 cells resulted in significant depletion of intracellular (IC) iron, and remarkably, upregulation of glucose transporter GLUT2 and insulin. Iron overloading, on the other hand, resulted in downregulation of GLUT2 and insulin in a PrP-dependent manner. Similar observations were noted in the brain, liver, and neuroretina of iron overloaded PrP but not PrP mice, indicating PrP-mediated modulation of insulin and glucose homeostasis through iron. Peripheral challenge with glucose and insulin revealed blunting of the response in iron-overloaded PrP relative to PrP mice, suggesting that PrP-mediated modulation of IC iron influences both secretion and sensitivity of peripheral organs to insulin. These observations have implications for Alzheimer's disease and diabetic retinopathy, known complications of type-2-diabetes associated with brain and ocular iron-dyshomeostasis.
朊病毒蛋白（PrP）是一种主要存在于神经元中的蛋白，已知其可调节小鼠模型中的葡萄糖稳态。我们在小鼠模型和人胰岛β细胞系 1.1B4 中探索了其潜在机制。我们报告了 PrP 在小鼠胰岛β细胞上的表达，它通过二价金属转运蛋白促进铁的摄取。因此，PrP 敲除小鼠（PrP）的胰腺铁储备明显低于野生型（PrP）对照。在 1.1B4 细胞中沉默 PrP 会导致细胞内（IC）铁显著耗竭，值得注意的是，葡萄糖转运蛋白 GLUT2 和胰岛素的表达上调。另一方面，铁超负荷以 PrP 依赖性方式导致 GLUT2 和胰岛素下调。在铁超负荷的 PrP 但不是 PrP 小鼠的大脑、肝脏和神经视网膜中观察到类似的现象，表明 PrP 通过铁介导对胰岛素和葡萄糖稳态的调节。外周给予葡萄糖和胰岛素后，铁超负荷的 PrP 相对于 PrP 小鼠的反应减弱，表明 PrP 介导的 IC 铁调节影响外周器官对胰岛素的分泌和敏感性。这些观察结果对阿尔茨海默病和糖尿病性视网膜病变具有重要意义，这两种疾病是与 2 型糖尿病相关的已知并发症，与脑和眼部铁稳态失调有关。
