Hepcidin derived from extrahepatic sources may also exert control over local iron fluxes within tissues in which hepcidin is produced. For example, the central nervous system is separated from the plasma by the blood-brain barrier, and circulating hepcidin may not be transported across this barrier. However, brain tissue itself was reported to express hepcidin, allowing the possibility of iron regulation independent of the systemic control.
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Mechanism of Hepcidin Action
Hepcidin acts by modulating cellular iron export through ferroportin to plasma and extracellular fluid. Ferroportin is both the hepcidin receptor and the only known cellular iron exporter in vertebrates. Ferroportin is expressed on cells that act as professional iron handlers in the body: duodenal enterocytes absorbing dietary iron, macrophages in liver and spleen recycling old erythrocytes, hepatocytes storing iron and placental trophoblasts transferring iron to the fetus during pregnancy. Ferroportin is also expressed in erythroid precursor cells, and it has been proposed that its presence enhances the sensitivity of precursors to systemic iron levels and helps determine their commitment to expansion and differentiation [8]. The complete loss of ferroportin expression in zebrafish and mouse models was shown to be embryonic lethal due to the inability of embryonic trophoblasts to transfer iron from the mother to the embryo. In the selective ferroportin knockout mice that preserved placental ferroportin, the newborn mice lacking ferroportin developed severe iron deficiency anemia due to low dietary iron absorption, and defective release of iron from hepatic storage and iron-recycling macrophages.
Posttranslational control of ferroportin levels by its ligand hepcidin is the major mode of ferroportin regulation. The binding of hepcidin to ferroportin triggers the internalization and degradation of the receptor-ligand complex. The binding likely involves disulfide exchange between one of disulfide bonds of hepcidin and the exofacial ferroportin thiol residue Cys326. Patients with C326S mutations develop early-onset iron overload, and the mutant ferroportin lost its ability to bind hepcidin in vitro. Once internalized, the hepcidin-ferroportin complex is degraded in lysosomes and cellular iron export ceases.
Ferroportin expression can also be regulated independently of hepcidin, by cellular iron content. Cellular iron has been shown to have an effect both at the transcriptional and translational level, the latter through a mechanism involving cytoplasmic iron-regulatory proteins and their corresponding binding sites in the 5′-region of one of the ferroportin mRNA isoforms.
Interestingly, the mechanism of iron transport by ferroportin has remained unexplored, and is one of the important challenges in advancing our understanding of cellular and systemic iron regulation.