Ferroportin-1, also known as solute carrier family 40 member 1 or iron-regulated transporter 1, is a protein that in humans is encoded by the SLC40A1gene, and is part of the Ferroportin Family. Ferroportin is a transmembrane protein that transports ironfrom the inside of a cell to the outside of the cell. Ferroportin is the only known iron exporter. After dietary iron is absorbed into the cells of the small intestine, ferroportin allows that iron to be transported out of those cells and into the bloodstream. Fpn also mediates the efflux of iron recycled from macrophages resident in the spleen and liver. Ferroportin is regulated by hepcidin, a hormone produced by the liver; hepcidin binds to Fpn and limits its iron-efflux activity, thereby reducing iron delivery to the blood plasma. Therefore, the interaction between Fpn and hepcidin controls systemic iron homeostasis.
Structure and function
Members of the ferroportin family consist of 400-800 amino acid residues, with a highly conservedhistidine at residue position 32, and exhibit 8-12 putative transmembrane domains. Human Fpn consists of 571 amino acid residues. When H32 is mutated in mice, iron transport activity is impaired. Recent crystal structures generated from a bacterial homologue of ferroportin revealed that the Fpn structure resembles that of major facilitator superfamily transporters. The prospective substrate binding site is located at the interface between the N-terminal and C-terminal halves of the protein, and is alternately accessible from either side of the cell membrane, consistent with MFS transporters. Ferroportin-mediated iron efflux is calcium-activated; studies of human Fpn expressed in Xenopus laevis oocytes demonstrated that calcium is a required cofactor for Fpn, but that Fpn does not transport calcium. Thus, Fpn does not function as an iron/calcium antiporter. The thermodynamic driving force for Fpn remains unknown.
Substrate profile
In addition to iron, ferroportin has been shown to transport cobalt & zinc, as well as nickel. Ferroportin may also function as a manganese exporter.
Tissue distribution
Ferroportin is found on the basolateral membranes of intestinal epithelia of mammals, including:
Ferroportin-1 plays an important role in neural tube closure and forebrain patterning. Mouse embryos lacking the Scl40a1 gene are aborted before gastrulation occurs, suggesting that the Fpn1 protein encoded is necessary and essential for normal embryonic development. Fpn1 is expressed in the syncytiotrophoblast cells in the placenta and visceral endoderm of mice at E7.5. Further, several retrospective studies have noted an increased incidence of spina bifida occurring after low maternal intake of iron during embryonic and fetal development. A study examining the consequences of several different mutations of the Slc40a1 mouse gene suggested that several serious neural tube and patterning defects were produced as a result, including spina bifida, exencephaly, and forebrain truncations, among others. Given the findings of studies to date, there appears to be significant evidence that intact iron transport mechanisms are critical to normal neural tube closure. Furthermore, other experiments have suggested that Fpn1 product and activity is required along the entire anterior-posterior axis of the animal to ensure proper closure of the neural tube.
Role in fertility
It is known that ferroportin gene is expressed at a low level in infertile women. Its mRNA levels were discovered to be down-regulated in these women, specifically in granulosa cells. What's more, low expression of ferroportin is also associated with infertility when some features like age and smoking habits are considered. It is also important to mention that, not only is ferroportin down-regulated in granulosa cells, but also in cervical cells of infertile women, and that the association between infertility and low ferroportin levels in these cells can be seen, again, when mRNA ferroportin levels was adjusted by age and smoking status.
Ferroportin is inhibited by hepcidin, which binds to ferroportin and internalizes it within the cell. This results in the retention of iron within enterocytes, hepatocytes, and macrophages with a consequent reduction in iron levels within the blood serum. This is especially significant with enterocytes which, when shed at the end of their lifespan, results in significant iron loss. This is part of the mechanism that causes anaemia of chronic disease; hepcidin is released from the liver in response to inflammatory cytokines, namely interleukin-6, which results in an increased hepcidin concentration and a consequent decrease in plasma iron levels. Ferroportin expression is also regulated by the IRP regulatory mechanism. If the iron concentration is too low, the IRP concentration increases, thus inhibiting the ferroportin translation. The ferroportin translation is also regulated by the micro RNA miR-485-3p.
Clinical significance
Mutations in the ferroportin gene are known to cause an autosomal dominant form of iron overload known as type IV haemochromatosis or Ferroportin Disease. The effects of the mutations are generally not severe but a spectrum of clinical outcomes are seen with different mutations. Ferroportin is also associated with African iron overload. Ferroportin and hepcidin are critical proteins for the regulation of systemic iron homeostasis.
