Lakhal-Littleton Samira, Wolna Magda, Chung Yu Jin, Christian Helen C, Heather Lisa C, Brescia Marcella, Ball Vicky, Diaz Rebeca, Santos Ana, Biggs Daniel, Clarke Kieran, Davies Benjamin, Robbins Peter A
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
Elife. 2016 Nov 29;5:e19804. doi: 10.7554/eLife.19804.
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.
铁调素是全身铁稳态的主要调节因子。它主要由肝脏产生，抑制肠道和脾脏中的铁输出蛋白铁转运蛋白，肠道和脾脏分别是铁吸收和再循环的部位。最近，我们证明铁转运蛋白也存在于心肌细胞中，并且其心脏特异性缺失会导致致命的心脏铁过载。铁调素也在心肌细胞中表达，其功能尚不清楚。为了确定心肌细胞铁调素的功能，我们构建了心肌细胞特异性缺失铁调素或敲入抗铁调素铁转运蛋白的小鼠。我们发现，虽然这两种模型都维持正常的全身铁稳态，但由于心肌细胞缺铁，它们仍会出现致命的收缩和代谢功能障碍。这些发现首次证明了铁调素在铁稳态中具有细胞自主作用。这增加了这样一种可能性，即这种功能在其他同时表达铁调素和铁转运蛋白的组织（如肾脏和大脑）中也可能很重要。
