Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis

Abstract

Despite its abundance in the environment, iron is poorly bioavailable and subject to strict conservation and internal recycling by most organisms. In vertebrates, the stability of iron concentration in plasma and extracellular fluid, and the total body iron content are maintained by the interaction of the iron-regulatory peptide hormone hepcidin with its receptor and cellular iron exporter ferroportin (SLC40a1). Ferroportin exports iron from duodenal enterocytes that absorb dietary iron, from iron-recycling macrophages in the spleen and the liver, and from iron-storing hepatocytes. Hepcidin blocks iron export through ferroportin, causing hypoferremia. During iron deficiency or after hemorrhage, hepcidin decreases to allow iron delivery to plasma through ferroportin, thus promoting compensatory erythropoiesis. As a host defense mediator, hepcidin increases in response to infection and inflammation, blocking iron delivery through ferroportin to blood plasma, thus limiting iron availability to invading microbes. Genetic diseases that decrease hepcidin synthesis or disrupt hepcidin binding to ferroportin cause the iron overload disorder hereditary hemochromatosis. The opposite phenotype, iron restriction or iron deficiency, can result from genetic or inflammatory overproduction of hepcidin.

Keywords: anemia; hemochromatosis; iron deficiency; iron overload; metal transport.

Figure 1

The key iron flows and compartments.

Figure 2

The interaction of hepcidin with ferroportin controls iron flows into plasma.

Figure 3

A current model of hepcidin (orange) interaction with ferroportin (blue) in which binding is dependent on iron (green). The framework of helices that make up ferroportin are depicted as cylinders connected by extracellular and intracellular disordered loops. The side chains that make up the binding sites for iron are shown. Modified from [14].

Figure 4

Iron, erythropoiesis and inflammation regulate hepcidin transcription through their effects on hepatocytes and by modulating the paracrine signaling between hepatic sinusoidal endothelium and hepatocytes.

Figure 5

Although ferroportin is evolutionarily ancient, the thiol cysteine required for hepcidin binding by ferroportin appears first in early vertebrate ferroportins. Cartilaginous fish ferroportin that contains the C326-equivalent is denoted with species name in red. Second ferroportin in cartilaginous fish that has another amino acid in this position is denoted with species name in blue. Invertebrate ferroportin lacks C326 and is denoted with species name in black.