近日,，國際知名學術期刊Hepatology在線發(fā)表了上海生科院營養(yǎng)所王福俤研究組的最新研究成果“Ferroportin 1 in hepatocytes and macrophages is required for the efficient mobilization of body iron stores”。該研究揭示了泵鐵蛋白Ferroportin 1(Fpn 1)在肝實質細胞鐵外排、鐵動員及維持機體鐵穩(wěn)態(tài)中的重要功能及機制,。
鐵作為人體必需微量元素,，其穩(wěn)態(tài)代謝維持需要多器官、多基因的精細調控,。鐵穩(wěn)態(tài)代謝中的四個重要環(huán)節(jié)是吸收,、轉運、鐵再循環(huán)和儲存,。鐵儲存的主要器官是肝臟,，肝臟又被稱為“鐵儲存器”。當機體缺鐵時,，肝實質細胞中儲存的鐵被有效動員出來,，滿足機體新陳代謝所需。雖然肝臟在鐵代謝中具有關鍵作用,，但肝細胞鐵外排通路以及肝細胞鐵外排與巨噬細胞鐵再循環(huán)間的復雜調控網(wǎng)絡還不清晰,。
王福俤研究員指導博士研究生張竹珍等利用Fpn 1肝實質細胞特異敲除小鼠(Fpn1Alb/Alb)及Fpn 1肝實質細胞和巨噬細胞雙敲除小鼠(Fpn1Alb/Alb；LysM/LysM)對肝細胞鐵外排通路開展了深入研究,。實驗發(fā)現(xiàn),，在正常狀態(tài)下只有少量鐵從肝實質細胞通過Fpn 1釋放到血液中；在缺鐵狀態(tài)時,，肝實質細胞Fpn 1負責從肝臟釋放大量鐵到血液中用于機體所需,。通過強化鐵飼料使小鼠肝臟儲存一定量的鐵，可有效預防缺鐵飼料飼養(yǎng)誘發(fā)貧血發(fā)生,；如果敲除肝細胞Fpn 1,，肝細胞鐵動員受阻，儲存的鐵不能被有效利用,，小鼠很容易表現(xiàn)出缺鐵性貧血癥狀,。另外，對于Fpn 1肝實質細胞和巨噬細胞雙敲小鼠Fpn1Alb/Alb,；LysM/LysM,，肝臟鐵動員及巨噬細胞鐵再循環(huán)均受阻，小鼠喂飼正常飼料時僅出現(xiàn)血清鐵輕度下降,；當用缺鐵飼料飼養(yǎng)時,，F(xiàn)pn1Alb/Alb；LysM/LysM小鼠很容易產(chǎn)生嚴重貧血癥狀,，提示腸道鐵吸收可以對肝鐵動員受損起代償作用,；實驗還發(fā)現(xiàn)Fpn1Alb/Alb；LysM/LysM小鼠腸道上皮細胞基底層的Fpn 1表達顯著高于對照小鼠,，特別是在缺鐵狀態(tài)下,，進一步證實腸道鐵吸收的重要作用,。
該項研究成果揭示了Fpn 1是介導肝細胞鐵外排的重要蛋白質，闡明了Fpn 1介導的肝臟鐵動員,、巨噬細胞鐵循環(huán)利用、腸道鐵吸收與鐵儲存之間相互調節(jié)互動來維持整體的鐵代謝平衡的調控網(wǎng)絡,，為鐵代謝紊亂相關疾病的治療提供了重要理論依據(jù),。
本項目得到國家科技部、國家自然科學基金委,、中國科學院及上海市科委等經(jīng)費資助,。（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.)
