An essential cell-autonomous role for hepcidin in cardiac iron homeostasis
An essential cell-autonomous role for hepcidin in cardiac iron homeostasis
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DOI：
10.7554/elife.19804
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发表时间：
2016-11-29
期刊：
影响因子：
7.7
通讯作者：
Robbins, Peter A.
中科院分区：
文献类型：
--
作者：
Lakhal-Littleton, Samira;Wolna, Magda;Robbins, Peter A.
海普西丁是全身铁稳态的主要调节者。它主要来自肝脏，抑制肠道和脾中的铁出口商铁转运蛋白，这两个部位分别是铁的吸收和循环。最近，我们证明在心肌细胞中也发现了铁蛋白，并且它的心脏特异性缺失会导致致命的心脏铁超载。海普西丁也在心肌细胞中表达，但其功能尚不清楚。为了确定心肌细胞海普西丁的功能，我们建立了心肌细胞特异性的海普西丁缺失的小鼠，或敲入了抗海普西丁的铁蛋白。我们发现，虽然两种模型都维持了正常的全身铁稳态，但由于心肌细胞铁缺乏，它们仍会发展为致命的收缩和代谢功能障碍。这些发现首次证明了海普西丁在铁稳态中的细胞自主作用。他们提出了这样一种可能性，即这种功能在同时表达海普西丁和铁蛋白的其他组织中也可能是重要的，比如肾脏和大脑。
Hepcidin is the master regulator of systemic iron homeostasis. Derived primarily from the liver, it inhibits the iron exporter ferroportin in the gut and spleen, the sites of iron absorption and recycling respectively. Recently, we demonstrated that ferroportin is also found in cardiomyocytes, and that its cardiac-specific deletion leads to fatal cardiac iron overload. Hepcidin is also expressed in cardiomyocytes, where its function remains unknown. To define the function of cardiomyocyte hepcidin, we generated mice with cardiomyocyte-specific deletion of hepcidin, or knock-in of hepcidin-resistant ferroportin. We find that while both models maintain normal systemic iron homeostasis, they nonetheless develop fatal contractile and metabolic dysfunction as a consequence of cardiomyocyte iron deficiency. These findings are the first demonstration of a cell-autonomous role for hepcidin in iron homeostasis. They raise the possibility that such function may also be important in other tissues that express both hepcidin and ferroportin, such as the kidney and the brain.