近日，国际知名学术期刊Hepatology在线发表了上海生科院营养所王福俤研究组的最新研究成果“Ferroportin 1 in hepatocytes and macrophages is required for the efficient mobilization of body iron stores”。该研究揭示了泵铁蛋白Ferroportin 1(Fpn 1)在肝实质细胞铁外排、铁动员及维持机体铁稳态中的重要功能及机制。
铁作为人体必需微量元素，其稳态代谢维持需要多器官、多基因的精细调控。铁稳态代谢中的四个重要环节是吸收、转运、铁再循环和储存。铁储存的主要器官是肝脏，肝脏又被称为“铁储存器”。当机体缺铁时，肝实质细胞中储存的铁被有效动员出来，满足机体新陈代谢所需。虽然肝脏在铁代谢中具有关键作用，但肝细胞铁外排通路以及肝细胞铁外排与巨噬细胞铁再循环间的复杂调控网络还不清晰。
王福俤研究员指导博士研究生张竹珍等利用Fpn 1肝实质细胞特异敲除小鼠(Fpn1Alb/Alb)及Fpn 1肝实质细胞和巨噬细胞双敲除小鼠(Fpn1Alb/Alb；LysM/LysM)对肝细胞铁外排通路开展了深入研究。实验发现，在正常状态下只有少量铁从肝实质细胞通过Fpn 1释放到血液中；在缺铁状态时，肝实质细胞Fpn 1负责从肝脏释放大量铁到血液中用于机体所需。通过强化铁饲料使小鼠肝脏储存一定量的铁，可有效预防缺铁饲料饲养诱发贫血发生；如果敲除肝细胞Fpn 1，肝细胞铁动员受阻，储存的铁不能被有效利用，小鼠很容易表现出缺铁性贫血症状。另外，对于Fpn 1肝实质细胞和巨噬细胞双敲小鼠Fpn1Alb/Alb；LysM/LysM，肝脏铁动员及巨噬细胞铁再循环均受阻，小鼠喂饲正常饲料时仅出现血清铁轻度下降；当用缺铁饲料饲养时，Fpn1Alb/Alb；LysM/LysM小鼠很容易产生严重贫血症状，提示肠道铁吸收可以对肝铁动员受损起代偿作用；实验还发现Fpn1Alb/Alb；LysM/LysM小鼠肠道上皮细胞基底层的Fpn 1表达显著高于对照小鼠，特别是在缺铁状态下，进一步证实肠道铁吸收的重要作用。
该项研究成果揭示了Fpn 1是介导肝细胞铁外排的重要蛋白质，阐明了Fpn 1介导的肝脏铁动员、巨噬细胞铁循环利用、肠道铁吸收与铁储存之间相互调节互动来维持整体的铁代谢平衡的调控网络，为铁代谢紊乱相关疾病的治疗提供了重要理论依据。
本项目得到国家科技部、国家自然科学基金委、中国科学院及上海市科委等经费资助。（生物谷Bioon.com）
doi:10.1002/hep.25746
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Ferroportin1 in hepatocytes and macrophages is required for the efficient mobilization of body iron stores
Zhuzhen Zhang, Fan Zhang, Xin Guo, Peng An, Yunlong Tao, Fudi Wang‡,*
The liver is a major site of iron storage where sequestered iron can be actively mobilized for utilization when needed elsewhere in the body. Currently, hepatocyte iron efflux mechanisms and their relationships to macrophage iron recycling during the control of whole-body iron homeostasis are unclear. We hypothesized that the iron exporter Ferroportin1 (Fpn1) is critical for both iron mobilization from hepatocytes and iron recycling from macrophages. To test this, we generated hepatocyte-specific Fpn1 deletion mice (Fpn1Alb/Alb), and mice that lacked Fpn1 in both hepatocytes and macrophages (Fpn1Alb/Alb;LysM/LysM). When fed a standard diet, Fpn1Alb/Alb mice showed mild hepatocyte iron retention. However, red blood cell counts (RBC) and hemoglobin levels were normal, indicating intact erythropoiesis. When fed an iron-deficient diet, Fpn1Alb/Alb mice showed impaired liver iron mobilization and anemia, with much lower RBC and hemoglobin levels than Fpn1flox/flox mice on the same diet. Using a strategy where mice were pre-loaded with differing amounts of dietary iron prior to iron deprivation, we determined that erythropoiesis in Fpn1Alb/Alb and Fpn1flox/flox mice depended on the balance between storage iron and iron demands. On a standard diet, Fpn1Alb/Alb;LysM/LysM mice displayed substantial iron retention in hepatocytes and macrophages, yet maintained intact erythropoiesis, implying a compensatory role for intestinal iron absorption. In contrast, when Fpn1Alb/Alb;LysM/LysM mice were fed an iron-deficient diet, they developed severe iron-deficiency anemia regardless of their iron storage status. Thus, Fpn1 is critical for both hepatocyte iron mobilization and macrophage iron recycling during conditions of dietary iron-deficiency. Conclusion: Our data reveal new insights into the relationships between Fpn1-mediated iron mobilization, iron storage, and intestinal iron absorption and how these processes interact to maintain systemic iron homeostasis. (Hepatology 2012.)
