Hepcidins

Figure 4. Simultaneous detection of HIV and Hepcidin (HEPC) SERS gene probe hybridizations.

There is one known pathway for cellular iron export, involving the export of iron into the plasma from the basolateral membrane of duodenal enterocytes, from macrophages, hepatocytes and a number of other cell types. This involves the protein known as IREG1 or ferroportin described already in Chapter 7. We will discuss ferroportin in more detail in the next section on iron homeostasis, since ferroportin is the target of hepcidin, a recently described iron regulatory peptide. 

Physiologically, body stores are maintained by extracting approximately 10% of the iron provided in a balanced diet and this corresponds to 1.5 mg each day for males and slightly more for females to compensate for pregnancy and menses. The trace element is derived from food by peptic digestion and after reduction the ferrous form crosses the enterocyte to be released at the serosal pole via the ferroportin-hepcidin mechanism to be transported, by plasma transferrin, to developing red cells in the marrow for haemoglobin synthesis. At the end of their life span effete erythrocytes are removed by the reticuloendothelial system in the spleen, bone marrow and the liver. 

Atanasin V, Manolescn B, Stoian 1. Hepcidin - central reg-nlator of iron metabohsm. Enr J Haematol 2006 Oct 17 [Epnb ahead of print]. 

Bony fish (winter flounder) Atlantic salmon Hepcidin-like Douglas et al. (2003)... 

Chang, W. T., Panb, C. Y., Rajanbabu, V., Cheng, C. W., and Chen, J. Y. (2011). Tilapia (Oreochromis mossambicus) antimicrobial peptide, hepcidin 1-5, shows antitumor activity in cancer cells. Peptides 32,342-352. 

Douglas, S. E., Gallant, J. W., Liebscher, R. S., Dacanay, A., and Tsoi, S. . M. (2003). Identification and expression analysis of hepcidin-like antimicrobial peptides in bony fish. Dev. Comp. Immunol. 27, 589-601. 

Zhang, J., Yan, Q., Ji, R., Zou, W., and Guo, G. (2009). Isolation and characterization of a hepcidin peptide from the head kidney of large yellow croaker, Pseudosciaena crocea. Fish Shellfish Immunol. 26, 864-870. 

Hybrid white striped bass hepcidin AMP arenicin-2 in aqueous Arenicola marina... 

Recent studies have characterized a 25-amino acid, 2- to 3-kd circulating peptide of hepatic origin called hepcidin. Hepcidin is thought to have anti-inflammatory properties perhaps related to its ability to downregulate iron stores. It has been shown that hepatic expression of hepcidin mRNA is significantly lower in patients with hemochromatosis when compared with controls. Hepcidin mRNA expression has also been shown to be decreased in HFE knockout mice. These data suggest that... 

Bridle KR, Frazer DM, Wilkins SJ, et al. Disrupted hepcidin regulation in HFE-associated he-... 

A Peptide Hormone Synthesized in Liver, Hepcidin, Coordinates Mammalian Iron Physiology... 

Recently, a peptide hormone known as hepcidin has been imphcated as a major circulating molecule that coordinates iron metabolism responses in the reticuloendothehal system and the duodenum. The presence of a circulating factor helps to explain how sites that are physically distant from one another, such as the duodenum and spleen, can coordinately regulate the amount of iron that they release into the bloodstream. Hepcidin negatively regulates iron absorption through the small intestine, iron transport across the placenta,... 

The hairpin-like structure has been conserved in the course of evolution, since it was found in many peptides isolated from various classes of arthropods, such as the primitive horseshoe crabs (tachyplesins [110,111] and polyphemusins [112,113]), arachnids (androctonin in scorpion [114] and gomesin in spider [115]) insect (thanatin [116]), in two classes of vertebrates, mammalian (protegrin [117,118], lactoferricin B [119] and hepcidins [120]) and fish (hepcidins [121]), and in plants (76-AMPl[122]). 

Finally, the hairpin-like peptides, hepcidins, isolated from human urine and liver [120], and from the gill of hybrid striped bass [121], are more complex, with eight cysteine residues forming four disulphide bridges. They form an unusual distorted P-sheet. Interestingly, besides their antimicrobial activity, hepcidins are the principal hormonal-regulators of iron homeostasis in humans [124]. 

Juvenile Hemochromatosis. Juvenile hemochromatosis is a rare disorder that resembles hereditary hemochromatosis clinically, but that has a much earlier average age of onset and a greater tendency to develop endocrine and cardiac manifestations than does hereditary hemochromatosis. It too is inherited, although the mutation is not in the HFE gene, but rather in an as-yet-unidentified gene on chromosome lq or in hepcidin. ... 

Nicolas G> Bennoun M, Devaux I, Beaumont C, Grandchamp B, Kahn A, Vaulont S. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci USA 2001 98 8780-5. 

Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot P, Loreal O. A new mouse fiver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem 2001 276 7811-9. 

FIGURE 22.2 Hepcidin and haemochromatosis. The activity of hepcidin is depicted, showing ferroportin as a target both on enterocytes and macrophages. Hepcidin binds to ferroportin triggering its internalisation and lysosomal degradation. (Adapted from Andrews, 2008.)... 

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