Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.
Haematologica. 2010 Mar;95(3):501-4. doi: 10.3324/haematol.2009.014399. Epub 2009 Sep 22.
Hepcidin, a circulating regulatory hormone peptide produced by hepatocytes, functions as the master regulator of cellular iron export by controlling the amount of ferroportin, an iron exporter present on the basolateral surface of intestinal enterocytes and macrophages. Hepcidin binding to ferroportin induces its internalization and degradation, resulting in cellular iron retention and decreased iron export. Whether hepatocytes express ferroportin that could be targeted by hepcidin has remained a subject of debate. Here, we describe a hepatocyte culture system expressing high levels of ferroportin, and demonstrate that both endogenously secreted and synthetic hepcidin are fully active in down-regulating membrane-associated ferroportin. In agreement with this result, ferroportin is stabilized in liver hepatocytes of hepcidin-deficient mice and accumulates in periportal areas, supporting the centrolobular iron deposition observed in these mice. In conclusion, we show that hepcidin can trigger ferroportin degradation in hepatocytes, which must be taken into account when considering hepcidin therapeutics.
亚铁肽，一种由肝细胞产生的循环调节激素肽，作为细胞铁输出的主要调节剂，通过控制铁输出蛋白（存在于肠上皮细胞和巨噬细胞的基底外侧表面）的数量来发挥作用。亚铁肽与铁输出蛋白结合会诱导其内化和降解，导致细胞内铁的保留和铁输出的减少。肝细胞是否表达可被亚铁肽靶向的铁输出蛋白一直存在争议。在这里，我们描述了一种表达高水平铁输出蛋白的肝细胞培养系统，并证明内源性分泌和合成的亚铁肽都能完全有效地下调膜结合的铁输出蛋白。与这一结果一致的是，亚铁肽在亚铁肽缺乏小鼠的肝实质细胞中稳定，并且在门脉周围区域积累，支持在这些小鼠中观察到的中央静脉周围铁沉积。总之，我们表明，亚铁肽可以在肝细胞中触发铁输出蛋白的降解，在考虑亚铁肽治疗时必须考虑这一点。
