Hepcidin

Hepcidin is a protein that in humans is encoded by the HAMP gene. Hepcidin is a key regulator of the entry of iron into the circulation in mammals.

In states in which the hepcidin level is abnormally high such as inflammation, serum iron falls due to iron trapping within macrophages and liver cells and decreased gut iron absorption. This typically leads to anemia due to an inadequate amount of serum iron being available for developing red cells. When the hepcidin level is abnormally low such as in hemochromatosis, iron overload occurs due to excessive ferroportin mediated iron influx.

Species
In lab mice hepcidin has been found to have anti-inflammatory properties. This is a negative feedback: it reduces the inflammation which caused the elevated hepcidin level.

Tissues
It is a peptide hormone synthesized mainly in the liver which was discovered in 2000. It reduces dietary iron absorption by reducing iron transport across the gut mucosa (enterocytes); it reduces iron exit from is_associated_with::macrophages, the main site of iron storage; and it reduces iron exit from the liver. In all three instances this is accomplished by reducing the transmembrane iron transporter is_associated_with::ferroportin.

Structure
Hepcidin exists as a is_associated_with::preprohormone (84 amino acids), is_associated_with::prohormone (60 amino acids), and is_associated_with::hormone (25 amino acids). Twenty- and 22-amino acid metabolites of hepcidin also exist in the urine. Deletion of 5 N-terminal amino acids results in loss of function. The conversion of prohepcidin to hepcidin is mediated by the prohormone convertase is_associated_with::furin. This conversion may be regulated by alpha-1 is_associated_with::antitrypsin.

Hepcidin is a tightly folded polypeptide with 32% is_associated_with::beta sheet character and a hairpin structure stabilized by 4 is_associated_with::disulfide bonds. The structure of hepcidin has been determined through solution NMR. NMR studies showed a new model for hepcidin: at ambient temperatures, the protein interconverts between two conformations, which could be individually resolved by temperature variation. The solution structure of hepcidin was determined at 325 K and 253 K in supercooled water. X-ray analysis of a is_associated_with::co-crystal with Fab revealed a structure similar to the high-temperature NMR structure.

Function


Hepcidin is a regulator of iron metabolism. Hepcidin inhibits iron transport by binding to the iron export channel is_associated_with::ferroportin which is located on the basolateral surface of gut is_associated_with::enterocytes and the plasma membrane of reticuloendothelial cells (is_associated_with::macrophages). Hepcidin ultimately breaks down the transporter protein in the is_associated_with::lysosome. Inhibiting ferroportin prevents iron from being exported and the iron is sequestered in the cells. By inhibiting ferroportin, hepcidin prevents is_associated_with::enterocytes from allowing iron into the is_associated_with::hepatic portal system, thereby reducing dietary iron absorption. The iron release from macrophages is also reduced by ferroportin inhibition. Increased hepcidin activity is partially responsible for reduced iron availability seen in anemia of chronic inflammation. such as renal failure.

Any one of several mutations in hepcidin result in is_associated_with::juvenile hemochromatosis. The majority of juvenile hemochromatosis cases are due to mutations in is_associated_with::hemojuvelin. Mutations in TMPRSS6 can cause anemia through dysregulation of Hepcidin

Hepcidin has antimicrobial activity against one E. Coli, two staph, one strep, and one fungal species.

Regulation
Hepcidin synthesis and secretion by the liver is controlled by iron stores within macrophages, is_associated_with::inflammation, hypoxia, and is_associated_with::erythropoiesis. Macrophages communicate with the hepatocyte to regulate hepcidin release into the circulation via eight different proteins: is_associated_with::hemojuvelin, heriditrary hemochromatosis protein, is_associated_with::transferrin receptor 2, bone morphogenic protein 6 (BMP6), matriptase-2, neogenin, BMP receptors, and is_associated_with::transferrin.

History
The peptide was initially named LEAP-1, for Liver-Expressed Antimicrobial Protein. Later, a peptide associated with inflammation was discovered, and named "hepcidin" after it was observed that it was produced in the liver ("hep-") and appeared to have bactericidal properties ("-cide" for "killing"). Although it is primarily synthesized in the liver, smaller amounts are synthesised in other tissues such as fat cells.

Hepcidin was first discovered in is_associated_with::human is_associated_with::urine and serum in 2000.

Soon after this discovery, researchers discovered that hepcidin production in mice increases in conditions of iron overload as well as in inflammation. Genetically modified mice engineered to overexpress hepcidin died shortly after birth with severe iron deficiency, again suggesting a central and not redundant role in iron regulation. The first evidence that linked hepcidin to the clinical condition known as the anemia of inflammation came from the lab of Nancy Andrews in Boston when researchers looked at tissue from two patients with liver is_associated_with::tumors with a severe is_associated_with::microcytic anemia that did not respond to is_associated_with::iron supplements. The tumor tissue appeared to be overproducing hepcidin, and contained large quantities of hepcidin mRNA. Removing the tumors surgically cured the anemia.

Taken together, these discoveries suggested that hepcidin regulates the absorption of iron into the body.

Clinical significance
There are many diseases where failure to adequately absorb iron contributes to is_associated_with::iron deficiency and is_associated_with::iron deficiency anaemia. The treatment will depend on the hepcidin levels that are present, as oral treatment will be unlikely to be effective if hepcidin is blocking enteral absorption, in which cases is_associated_with::parenteral iron treatment would be appropriate. Studies have found that measuring hepcidin would be of benefit to establish optimal treatment, although as this is not widely available, is_associated_with::C-reactive protein (CRP) is used as a surrogate marker.

Beta-thalassemia is one of the most common is_associated_with::congenital is_associated_with::anemias arising from partial or complete lack of β-globin synthesis. Excessive iron absorption is one of the main features of is_associated_with::β-thalassemia and can lead to severe morbidity and mortality. The serial analyses of β-thalassemic mice indicate is_associated_with::hemoglobin levels decreases over time, while the concentration of iron in the is_associated_with::liver, is_associated_with::spleen, and is_associated_with::kidneys markedly increases. The overload of iron is associated with low levels of hepcidin. It was found that patients with is_associated_with::β-thalassemia also have low hepcidin levels. The observations led researchers to hypothesize that more iron is absorbed in is_associated_with::β-thalassemia than is required for is_associated_with::erythropoiesis and whether increasing the concentration of hepcidin in the body of such patients might be therapeutic, limiting iron overload. It was demonstrated that a moderate increase in expression of hepcidin in β-thalassemic mice limits iron overload, decreases formation of insoluble is_associated_with::membrane-bound globins and reactive oxygen species, and improves anemia. Mice with increased hepcidin expression also demonstrated an increase in the lifespan of their is_associated_with::red cells, reversal of ineffective is_associated_with::erythropoiesis and is_associated_with::splenomegaly, and an increase in total is_associated_with::hemoglobin levels. This data suggests that is_associated_with::therapeutics that would increase hepcidin levels or act as hepcidin is_associated_with::agonists might help treat the abnormal iron absorption in individuals with is_associated_with::β-thalassemia and related disorders. Bolus doses of vitamin D2 (100,000iu) decrease circulating hepcidin rapidly, thereby enhancing or increasing iron levels in the bloodstream. Circulating hepcidin began to decline 2 hours after a bolus of vitamin D2 before circulating 25(OH)D begins to rise. Optimal function of hepcidin would seem to be predicated upon adequate presence of vitamin D in the blood.