|hepcidin antimicrobial peptide|
|Locus||Chr. 19 q13.1|
Hepcidin is a key regulator of the entry of iron into the circulation in mammals, including humans. 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 macrophages, the main site of iron storage; and it reduces iron exit from the liver. In all three instances this is accomplshed by reducing the transmembrane iron transporter ferroportin.
In states in which the hepcidin level is abnormally high such as inflammation, serum iron falls due to decreased gut iron absorption and iron trapping within macrophages and liver cells. 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.
The gene that encodes for hepcidin in humans is named HAMP, an abbreviation for ""hepcidin antimicrobial peptide".
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.
Hepcidin exists as a preprohormone (84 amino acids), prohormone (60 amino acids), and 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 furin. This conversion may be regulated by alpha-1 antitrypsin.
Hepcidin is a tightly folded polypeptide with 32% beta sheet character and a hairpin structure stabilized by 4 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 co-crystal with Fab revealed a structure similar to the high-temperature NMR structure.
Hepcidin is secreted mainly by the liver and is considered the "master regulator" of iron metabolism. Hepcidin inhibits iron transport by binding to the iron export channel ferroportin, which is located on the basolateral surface of gut enterocytes and the plasma membrane of reticuloendothelial cells (macrophages). Inhibiting ferroportin prevents iron from being exported and the iron is sequestered in the cells. By inhibiting ferroportin, hepcidin prevents enterocytes from allowing iron into the 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.
Hepcidin has antimicrobial activity against one E. Coli, two staph, one strep, and one fungal species.
Hepcidin synthesis and secretion by the liver is controlled by iron stores within macrophages, inflammation, hypoxia, and erythropoiesis. Macrophages communicate with the hepatocyte to regulate hepcidin release into the circulation via eight different proteins: hemojuvelin, heriditrary hemochromatosis protein, transferrin receptor 2, bone morphogenic protein 6 (BMP6), matriptase-2, neogenin, BMP receptors, and transferrin.
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 synthesised in the liver, smaller amounts have been found to be synthesised in other tissues such as fat cells.
Hepcidin was first discovered in human urine and serum in 2000. Most understandings of hepcidin regulation and action comes from in vitro and mice studies that often use hepcidin mRNA expression as a read-out. Carrying out studies in humans is difficult due to the lack of suitable hepcidin assay. With the recent developments of assays to measure hepcidin in serum and urine, new opportunities to study the regulation of hepcidin in humans have arisen. Only a few laboratories are able to perform these assays at the current moment. The aim of the studies is to discuss insights into hepcidin regulation obtained from recent clinical studies in the light of findings from in vitro and mice studies. Ongoing studies in humans should provide us with more information on the etiology of iron metabolism disorders in order to create new therapeutic strategies and improve differential diagnosis protocols for these diseases.
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 tumors with a severe microcytic anemia that did not respond to 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.
There are many diseases where failure to adequately absorb iron contributes to iron deficiency and 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 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, C-reactive protein (CRP) is used as a surrogate marker.
Beta-thalassemia is one of the most common congenital anemias arising from partial or complete lack of β-globin synthesis. Excessive iron absorption is one of the main features of β-thalassemia and can lead to severe morbidity and mortality. The serial analyses of β-thalassemic mice indicate hemoglobin levels decreases over time, while the concentration of iron in the liver, spleen, and kidneys markedly increases. The overload of iron is associated with low levels of hepcidin. It was found that patients with β-thalassemia also have low hepcidin levels. The observations led researchers to hypothesize that more iron is absorbed in β-thalassemia than is required for 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 membrane-bound globins and reactive oxygen species, and improves anemia. Mice with increased hepcidin expression also demonstrated an increase in the lifespan of their red cells, reversal of ineffective erythropoiesis and splenomegaly, and an increase in total hemoglobin levels. This data suggests that therapeutics that would increase hepcidin levels or act as hepcidin agonists might help treat the abnormal iron absorption in individuals 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.
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- M. Hewison, B.W. HOllis, unpublished data, 2013
- The Role of the Parent Compound vitamin D with Respect to Metabolism and Function: Why Clinical Dose Intervals Can Affect Clinical Outcomes; J Clin Endocrinol Metab, December 2013, 98(12):4619-4628
- hepcidin at the US National Library of Medicine Medical Subject Headings (MeSH)
- Intrinsic LifeSciences - Hepcidin Research Facility, The BioIron Company
- Hepcidinanalysis.com - Service for Hepcidin measurements: Scientific Research, Patients and Clinical Trials
- Protein Data Bank Page