Hepcidin and Ferroportin

Iron is an essential micronutrient that is toxic because of its ability to form oxygen free radicals that can damage macromolecules. It is this property of iron that makes it essential for total body iron content be controlled and tissue be protected while iron is being transported from the sources of iron (macrophages and enterocytes) to consumers of iron (erythroid cells and syncytitrophoblast). Iron has no significant excretory pathways controlling absorption is the only way to check against iron overload. Ferroportin the only known transporter of iron and hepcidin a peptide that binds and degrades ferroportin are central to control body iron content. Mutations in both have been implicated in haemochromatosis.

Ferroportin

Ferroportin, the product of the SLC40A1 (Solute carrier family 40 (iron-regulated transporter) member 1) gene (OMIM: 604653) situated at chromosome 2q32.2,  is the only known iron transporter. It is a 571 amino acid peptide with a yet to be defined. It is believed to contain between 9-12 transmembrane domains. Ferroportin is expressed on the macrophages, Küpffer cells, hepatocytes, intestinal enterocytes and placental cells. All these cells are involved in iron transport.

Regulation of expression
  1. Transcriptional level: IRE in the untranslated 5′ region. The effect or ion loading is tissue specific. Iron loading increases the expression of ferroportin in liver cells and macrophages . Iron deficiency increases the expression of ferroportin the duodenum. These findings are consistent with the functions of the hepatocytes and macrophages on one hand (releasing iron at a rate dictated by iron deficiency) and the duodenum on the other (transporting iron to the lamina propria in the presence of iron deficiency).
  2. Post-translational Modification: Hepcidin binds to and phosphorylation ferroportin leading to internalisation and  degradation of ferroportin.
Mutations in Ferroportin Gene

Mutations in the Ferroportin Gene result in haemochromatosis type 4 or ferroportin disease.  Mutations result in synthesis of ferroportin molecules that can not bind hepcidin

Hepcidin

Hepcidin (Hepcidin Antimicrobial Peptide, HAMP) is an 25 amino acid peptide secreted predominantly by the liver. It is encoded by the HAMP (OMIM 60464)gene located in chromosome 19q13.12. It is synthesised as an 84 amino acid precursor. It has 8 cysteine residues and four disulphide bond. It circulates in the plasma associated with α2-macroglobulin and albumin.

Function of Hepcidin

Hepcidin  was firs identified as an antimicrobial peptide but is now known to the main regulator of iron metabolism. Hepcidin binds ferroportin to bring about its internalisation and degradation. Hepcidin impairs release or iron from the cells.  Hepcidin levels are decreased by depletion of iron stores, phlebotomy, haemolysis and elevated erythropoietin levels. Hepcidin regulates the absorption and distribution of iron

  1. Absorption of Iron: Hepcidin levels increase iron overload resulting in decreased ferroportin expression on the basilateral aspect of the duodenal cell.  The cell is not able to transport absorbed iron to the plasma and addition of more iron to the body iron pool is controlled.
  2. Distribution of Iron: Increased hepcidin in states of iron overload decreases the ferroportin expression of macrophages and hepatocytes. Hepcidin prevents entry of recycled iron from the macrophages and stored iron from the hepatocytes into the plasma.

Mice with disruption id the USF2 gene have a complete suppression of hepcidin levels and develop an illness like human haemochromatosis. Inducing over expression of hepcidin by placing the gene under transgenic control of the liver-specific transthyretin promoter resulted in a mice that were severely anaemic with hypochromia and microcytosis that survived only a few hours (Proc Natl Acad Sci USA2002;99(7):4596-4601).

Regulation of Hepcidin
  1. Positive Regulators: Bone morphogenic Proteins 6 (BPM6), hemojuvelin (HJV), mothers against decapentaplegic homolog 4 (SMAD4), Transferrin receptor 2 (TFR2) and haemochromatois protein (HFE)
  2. Negative Regulators: TMPRSS6
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