Treating iron overload with hepcidin

Hepcidin overexpression may correct the molecular defect in a murine model of hemochromatosis, not only blocking intestinal iron hyperabsorption and inappropriately high macrophage release, but also inducing redistribution of the hepatocyte-stored iron.

The liver peptide hepcidin plays the role of negative regulator of systemic iron homeostasis both in mice and humans. The synthesis of hepcidin is increased in iron overload and inflammation and decreased in iron deficiency.¹  Hepcidin deficiency (either absolute or relative to iron overload) is the hallmark of hemochromatosis,²  and hepcidin homozygous mutations cause the most severe, juvenile form of the disease.³  Hepcidin binds the transmembrane iron exporter ferroportin, and induces its internalization and degradation.⁴  In duodenum and macrophages, where ferroportin is mostly expressed, this translates into decreased iron export to circulating transferrin. Accordingly, hepcidin might be effective in treating hemochromatosis by decreasing dietary iron acquisition, but a positive effect on liver iron stores was unproved.

Viatte and colleagues show that the overexpression of hepcidin might be beneficial even in established iron overload. They have developed a conditional transgenic mouse model using a tetracycline-dependent system, which allows induction of hepcidin expression in response to tetracycline treatment. This avoids death at birth from severe iron deficiency that occurs in transgenic animals with constitutive hepcidin expression.⁵ 

In normal mice, short-term and 3-week hepcidin induction cause, respectively, transient hypoferremia and iron-deficient anemia, as observed in acute and chronic inflammation. To explore the effect of hepcidin in iron overload, transgenic hepcidin-inducible mice were crossed with Hfe^–/– mice, a model of hemochromatosis. While control Hfe^–/– mice have high serum and hepatocyte iron and low spleen and duodenum ferritin, hepcidin-inducible Hfe^–/– mice, after 3 weeks of doxycycline treatment, showed hypoferremia, signs of iron-restricted erythropoiesis and iron retention in enterocytes and spleen macrophages. Reduction of ferroportin expression in these cells was documented by immunoblotting and immunohistochemistry. Liver iron concentration remained rather constant, but surprisingly, iron was redistributed from hepatocytes to Kupffer cells.

Although the mechanisms underlying this phenomenon remain unexplored, shifting iron to macrophages, where iron is well tolerated, may be of benefit in iron overload. This also suggests a distinct regulation of ferroportin in hepatocytes compared with enterocytes and macrophages. Either hepcidin has no autocrine effect or this effect is overtaken by other regulatory mechanisms. Hepatocytes physiologically accumulate iron, but must be protected from iron excess. Iron-dependent hepcidin synthesis serves this purpose, through degradation of the cellular iron exporter, but, to reduce hepatocyte accumulation, degradation of hepatocyte ferroportin should be kept limited.

Finally, hepcidin-expressing Hfe^–/– mice had limited iron supply for erythropoiesis. It seems that an erythroid marrow signal is required to mobilize hepatocyte iron, as likely occurs after phlebotomy (ie, the standard hemochromatosis treatment). Globally, these results suggest that hepcidin not only limits excessive body iron accumulation, but might favor the efflux of hepatocyte iron, increasing the erythropoiesis demands in conditions of blocked intestinal and macrophage iron supply. How to achieve a balance between hepatocyte iron reduction and development of anemia will be crucial in hepcidin treatment. ▪