Abstract
Hepcidin is a small cysteine rich peptide that regulates the sole known cellular iron exporter, ferroportin, effectively controlling iron metabolism. Contrary to humans, where a single hepcidin exists, many fish have two functionally distinct hepcidin types, despite having a single ferroportin gene. This raises the question of whether ferroportin is similarly regulated by the iron regulator Hamp1 and the antimicrobial Hamp2. In sea bass (Dicentrarchus labrax), iron overload prompted a downregulation of ferroportin, associated with an upregulation of hamp1, whereas an opposite response was observed during anemia, with no changes in hamp2 in either situation. During infection, ferroportin expression decreased, indicating iron withholding to avoid microbial proliferation. In vivo administration of Hamp1 but not Hamp2 synthetic peptides caused significant reduction in ferroportin expression, indicating that in teleost fish with two hepcidin types, ferroportin activity is mediated through the iron-regulator Hamp1, and not through the dedicated antimicrobial Hamp2. Additionally, in vitro treatment of mouse macrophages with fish Hamp1 but not Hamp2 caused a decrease in ferroportin levels. These results raise questions on the evolution of hepcidin and ferroportin functional partnership and open new possibilities for the pharmaceutical use of selected fish Hamp2 hepcidins during infections, with no impact on iron homeostasis.
Highlights
Hepcidin, a small cysteine rich peptide originally characterized as an antimicrobial peptide, is currently considered the key regulator of iron metabolism[1,2,3]
This role is exerted through the regulation of Ferroportin (FPN1), known as iron-regulated gene 1 (IREG1), metal transporter protein 1 (MTP1), solute carrier family 11 member 3 (SLC11A3) or solute carrier family 40 member 1 (SLC40A1), a transmembrane protein that has been independently identified by three distinct research groups as the sole known cellular iron exporter[4,5,6]
Ferroportin plays a critical role in iron homeostasis, being expressed in all sites involved in iron export to the plasma, including the basolateral membranes of duodenal enterocytes[4,6,8], hepatocytes[9], reticuloendothelial macrophages[8] and the embryonic syncytiotrophoblasts[6]
Summary
A small cysteine rich peptide originally characterized as an antimicrobial peptide, is currently considered the key regulator of iron metabolism[1,2,3] This role is exerted through the regulation of Ferroportin (FPN1), known as iron-regulated gene 1 (IREG1), metal transporter protein 1 (MTP1), solute carrier family 11 member 3 (SLC11A3) or solute carrier family 40 member 1 (SLC40A1), a transmembrane protein that has been independently identified by three distinct research groups as the sole known cellular iron exporter[4,5,6]. In order to identify the region involved with hepcidin binding, several studies have analyzed the functional consequences of mutations in ferroportin, and depending on the amino acid substitution or the assay used, the results range from innocuous to resistance to hepcidin degradation or total loss of function[21,22,25,28,30,31,32,33,34]
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