Ferroportin1 in hepatocytes and macrophages is required for the efficient mobilization of body iron stores in mice
Ferroportin1 in hepatocytes and macrophages is required for the efficient mobilization of body iron stores in mice
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DOI：
10.1002/hep.25746
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发表时间：
2012-09
期刊：
影响因子：
13.5
通讯作者：
Zhuzhen Zhang;Fan Zhang;Xin Guo;Peng-cheng An;Yunlong Tao;Fudi Wang
中科院分区：
文献类型：
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作者：
Zhuzhen Zhang;Fan Zhang;Xin Guo;Peng-cheng An;Yunlong Tao;Fudi Wang
肝脏是铁存储的主要部位，在这里，隔离的铁可以被积极地动员起来，以便在身体其他地方需要时被利用。目前，在控制全身铁稳态的过程中，肝细胞铁外流机制及其与巨噬细胞铁循环的关系尚不清楚。我们假设铁出口蛋白1(Fpn1)对从肝细胞动员铁和从巨噬细胞回收铁都是关键的。为了测试这一点，我们产生了肝细胞特异性Fpn1缺失小鼠(Fpn1Alb/Alb)和在肝细胞和巨噬细胞中都缺乏Fpn1的小鼠(Fpn1Alb/Alb；LysM/LysM)。当饲喂标准饲料时，Fpn1Alb/Alb小鼠表现出轻微的肝细胞铁滞留。然而，红细胞(RBC)计数和血红蛋白(Hb)水平正常，表明完整的红细胞生成。当饲喂缺铁饲料时，Fpn1Alb/Alb小鼠表现出肝铁动员受损和贫血，RBC和Hb水平远低于相同饮食的Fpn1flx/Flox小鼠。采用一种策略，在缺铁之前给小鼠预加不同量的膳食铁，我们确定Fpn1Alb/Alb和Fpn1flx/Flox小鼠的红细胞生成依赖于储存铁和铁需求之间的平衡。在标准饮食中，Fpn1Alb/Alb；LysM/LysM小鼠显示出大量的铁滞留在肝细胞和巨噬细胞中，但仍保持完整的红细胞生成，这意味着肠道铁吸收的补偿作用。相比之下，当Fpn1Alb/Alb；LysM/LysM小鼠被喂养缺铁饮食时，无论它们的铁储存状况如何，它们都会患上严重的缺铁性贫血。因此，在膳食缺铁的情况下，Fpn1对肝细胞铁动员和巨噬细胞铁循环都是至关重要的。结论：我们的数据揭示了Fpn1介导的铁动员、铁储存和肠道铁吸收之间的关系以及这些过程如何相互作用以维持全身铁平衡。(《肝病》2012；56：961-971)
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 (RBC) counts and hemoglobin (Hb) 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 Hb levels than Fpn1flox/flox mice on the same diet. Using a strategy where mice were preloaded with differing amounts of dietary iron before 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;56:961–971)