Hepcidin - the Iron Regulatory Hormone
The existence of an iron regulatory hormone was postulated primarily to account for the observed interactions between the anatomically distinct sites of iron absorption, recycling and utilisation. Hepcidin is now acknowledged to be the main iron regulatory hormone. It is a 25-amino acid peptide exclusively synthesized by the liver, initially identified as part of a search for novel antimicrobial peptides.1 There was no indication that it had an additional role in iron metabolism until 2001, when mouse studies were published showing that hepatic hepcidin mRNA synthesis was induced by iron loading.2
Hepcidin was first isolated from human urine and named on the basis of its site of synthesis (hep-) and its in-vitro antibacterial properties (-cidin). In human urine, the predominant form contains 25 amino acids, although shorter 22 and 20 amino acid peptides are also present. The main peptide is notable for containing eight cysteine residues linked as four disulphide bridges resulting in a molecule with a simple hairpin structure and the bridges in a ladder-like configuration. This structure is characteristic of peptides capable of disrupting bacterial membranes and is similar to other antimicrobial peptides. This article will briefly summarise recent work identifying hepcidin as a key player in iron metabolism and its role as an iron regulatory hormone. More detailed information is presented in a review article by Ganz.3 More of the manifold functions of hepcidin are being regularly discovered, and it will be some time before the complete repertoire of functions of this versatile peptide are established.
Hepcidin model of HFE haemochromatosis
The discovery of the hepcidin peptide and characterisation of its gene, HAMP,4 has led to the revision of previous models for the regulation of iron homeostasis and the realisation that the liver plays a key role in determining iron absorption from the gut and iron release from recycling and storage sites. Perhaps the most striking example has been to change the pathogenic model of HFE-related hereditary haemochromatosis from the crypt-programming model centred on the duodenal absorptive enterocyte to the hepcidin model centred on the hepatocyte.5,6 In summary, the hepcidin model proposes that the rate of iron efflux into the plasma depends primarily on the plasma level of hepcidin; when iron levels are high the synthesis of hepcidin increases and the release of iron from enterocytes and macrophages is diminished. Conversely when iron stores drop, the synthesis of hepcidin is down-regulated and these cells release more iron.
Hepcidin and ferroportin interaction
In order to describe the postulated major role of hepcidin it is necessary to understand the function of ferroportin, a protein first characterised in 2000. Ferroportin is the major iron export protein located on the cell surface of enterocytes, macrophages and hepatocytes, the main cells capable of releasing iron into plasma for transport by transferrin.7
The major iron recycling pathway is centred on the degradation of senescent red cells by reticuloendothelial macrophages located in bone marrow, hepatic Kupffer cells and spleen. The exit of iron from these macrophages is controlled by ferroportin. The role of the hepatocyte is central to the action of ferroportin, because the hepatocyte is proposed to sense body iron status and either release or down-regulate hepcidin, which then interacts with ferroportin to modulate the release of cellular iron. Hepcidin directly binds to ferroportin and decreases its functional activity by causing it to be internalized from the cell surface and degraded.8
Increased hepcidin synthesis
Increased hepcidin synthesis is thought to mediate iron metabolism in two clinically important circumstances, shown schematically in Figure 1. In individuals who do not harbour mutations causing haemochromatosis, the hepatocyte is thought to react to either an increase in iron saturation of transferrin or to increased iron stores in hepatocytes themselves, by inducing the synthesis of hepcidin by an as yet unknown mechanism. Thus the physiological response to iron overload under normal circumstances would be the hepcidin mediated shut down of iron absorption (enterocyte), recycling (macrophage) and storage (hepatocyte).
Induction of liver hepcidin synthesis decreases iron export from absorptive cells (enterocytes) recycling cells (macrophages) and storage cells (hepatocytes).
The synthesis and release of hepcidin is also rapidly mediated by bacterial lipopolysaccaride and cytokine release, especially interleukin-6. Thus the hepcidin gene is an acute-phase responsive gene which is overexpressed in response to inflammation. Cytokine mediated induction of hepcidin caused by inflammation or infection is now thought to be responsible for the anaemia of chronic disease, where iron is retained by the key cells that normally provide it, namely enterocytes, macrophages and hepatocytes. Retention of iron leads to the hallmark features of the anaemia of chronic disease, low transferrin saturation, iron-restricted erythropoeisis and mild to moderate anaemia.9 The nature of the hepcidin receptor is presently unknown, however an exciting future prospect may be the development of agents to block the receptor with the aim of treating the anaemia of chronic disease, a common often intractable clinical problem.
Decreased hepcidin synthesis
Down-regulation of hepcidin synthesis results in increased iron release, which arises in the two situations shown schematically in Figure 2. The main causes of non-HFE haemochromatosis are mutations in either ferroportin, transferrin receptor 2, hepcidin or hemojuvelin genes. Classical HFE haemochromatosis, and all types of non-HFE haemochromatosis thus far studied with the exception of ferroportin related haemochromatosis, are characterised by inappropriate hepcidin deficiency. In these circumstances, hepatocytes become iron loaded, because their uptake of transferrin bound iron from the circulation is assumed to exceed that of ferroportin mediated export. Hepcidin deficiency causes increased ferroportin mediated iron export, resulting in increased enterocyte absorption of iron and perhaps quantitatively more important, enhanced export of recycled iron onto plasma transferrin by macrophages. Hepcidin is also suppressed in thalassaemic syndromes, both β thalassaemia major and intermedia and congenital dyserythropoetic anaemic type 1, where iron absorption is inappropriately stimulated despite the presence of massive iron overload.10
Down-regulation of liver hepcidin synthesis increases iron export from absorptive cells (enterocytes) recycling cells (macrophages) and storage cells (hepatocytes). The box labelled ‘HFE- and Non-HFE haemochromatosis. (not FP disease)’ refers to HFE- and non-HFE haemochromatosis with the sole exception of ferroportin disease.
As shown in Figure 2, anaemia and hypoxia both trigger a decrease in hepcidin levels. These discoveries were made in animal models and need to be further studied to show they are applicable in humans. Two animal models of anaemia in mice were used to demonstrate a dramatic decrease in hepcidin synthesis where anaemia was provoked either by excessive bleeding or haemolysis.11 This is postulated to permit the rapid mobilisation of iron from macrophages and enterocytes necessary to allow for the increased erythropoietic activity triggered by erythropoietin release. The same study showed down-regulation of hepcidin synthesis can be triggered by hypoxia alone, and mice housed in hypobaric hypoxia chambers simulating an altitude of 5,500 m also showed a rapid decrease in hepcidin.
In summary, hepcidin provides a unifying hypothesis to explain the behaviour of iron in two diverse but common clinical conditions, the anaemia of chronic disease and both HFE and non-HFE haemochromatosis. The pathophysiology of hepcidin has been sufficiently elucidated to offer promise of therapeutic intervention in both of these situations. When the hepcidin receptor is characterised, an exciting future prospect may be the development of agents to block the receptor with the aim of treating the anaemia of chronic disease. Administering either hepcidin or an agonist could treat haemochromatosis, where the secretion of hepcidin is abnormally low.
Notes
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Footnotes
Competing Interests: None declared.