The liver hormone hepcidin regulates systemic iron homeostasis to provide enough iron for vital processes while limiting toxicity. Hepcidin acts by degrading its receptor ferroportin (encoded by Slc40a1) to decrease iron export to plasma. Iron controls hepcidin production in part by inducing liver endothelial cells (LECs) to produce bone morphogenetic proteins (BMPs) that activate hepcidin transcription in hepatocytes. Here, we used in vitro and in vivo models to investigate whether ferroportin contributes to LEC intracellular iron content to modulate BMP expression and, thereby, hepcidin. Quantitative proteomics of LECs from mice fed different iron diets demonstrated an inverse relationship between dietary iron and endothelial ferroportin expression. Slc40a1 knockdown primary mouse LECs and endothelial Slc40a1 knockout mice exhibited increased LEC iron and BMP ligand expression. Endothelial Slc40a1 knockout mice also exhibited altered systemic iron homeostasis with decreased serum and total liver iron but preserved erythropoiesis. Although endothelial Slc40a1 knockout mice had similar hepcidin expression to control mice, hepcidin levels were inappropriately high relative to iron levels. Moreover, when iron levels were equalized with iron treatment, hepcidin levels were higher in endothelial Slc40a1 knockout mice than in controls. Finally, LEC ferroportin levels were inversely correlated with hepcidin levels in multiple mouse models, and treatment of hepcidin-deficient mice with mini-hepcidin decreased LEC ferroportin expression. Overall, these data show that LEC ferroportin modulates LEC iron and consequently BMP expression to influence hepcidin production. Furthermore, LEC ferroportin expression is regulated by hepcidin, demonstrating a bidirectional communication between LECs and hepatocytes to orchestrate systemic iron homeostasis.

中文翻译：

---

铁调素-铁转运蛋白轴调节肝内皮细胞 BMP 表达以影响小鼠的铁稳态


肝脏激素铁调素调节全身铁稳态，为重要过程提供足够的铁，同时限制毒性。铁调素通过降解其受体铁转运蛋白（由 Slc40a1 编码）来减少铁向血浆的输出。铁通过诱导肝内皮细胞 （LEC） 产生激活肝细胞中铁调素转录的骨形态发生蛋白 （BMP） 来部分控制铁调素的产生。在这里，我们使用体外和体内模型来研究铁转运蛋白是否有助于 LEC 细胞内铁含量以调节 BMP 表达，从而调节铁调素。喂食不同铁饮食小鼠的 LECs 的定量蛋白质组学表明，膳食铁与内皮铁转运蛋白表达呈负相关。Slc40a1 敲低原代小鼠 LEC 和内皮 Slc40a1 敲除小鼠表现出 LEC 铁和 BMP 配体表达增加。内皮 Slc40a1 敲除小鼠也表现出全身铁稳态改变，血清和总肝铁降低，但红细胞生成保留。尽管内皮 Slc40a1 敲除小鼠与对照小鼠具有相似的铁调素表达，但铁调素水平相对于铁水平不适当地高。此外，当铁水平与铁处理相等时，内皮 Slc40a1 敲除小鼠的铁调素水平高于对照组。最后，在多个小鼠模型中，LEC 铁转运蛋白水平与铁调素水平呈负相关，用微型铁调素治疗铁调素缺陷小鼠降低了 LEC 铁转运蛋白的表达。总体而言，这些数据表明 LEC 铁转运蛋白调节 LEC 铁，从而调节 BMP 表达以影响铁调素的产生。 此外，LEC 铁转运蛋白表达受铁调素调节，表明 LEC 和肝细胞之间存在双向通讯，以协调全身性铁稳态。