| Hepcidin | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 Solution structure of hepcidin-25.[5] | |||||||||
| Identifiers | |||||||||
| Symbol | Hepcidin | ||||||||
| Pfam | PF06446 | ||||||||
| InterPro | IPR010500 | ||||||||
| SCOP2 | 1m4f /SCOPe /SUPFAM | ||||||||
| OPM superfamily | 153 | ||||||||
| OPM protein | 1m4e | ||||||||
| |||||||||
| hepcidin antimicrobial peptide | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | HAMP | ||||||
| NCBI gene | 57817 | ||||||
| HGNC | 15598 | ||||||
| OMIM | 606464 | ||||||
| RefSeq | NM_021175 | ||||||
| UniProt | P81172 | ||||||
| Other data | |||||||
| Locus | Chr. 19q13.1 | ||||||
| |||||||
Hepcidin is aprotein that in humans is encoded by theHAMP gene. Hepcidin is a key regulator of the entry ofiron into the circulation in mammals.[6]
During conditions in which the hepcidin level is abnormally high, such asinflammation, serum iron falls due to iron trapping withinmacrophages andliver cells and decreased gut iron absorption. This typically leads to anemia due to an inadequate amount of bloodserum iron being available for developingred blood cells. When the hepcidin level is abnormally low, such as inhemochromatosis, iron overload occurs due to increasedferroportin mediated iron efflux from storage and increased gut iron absorption.
Hepcidin is initially synthesized as an 84-amino acidpreprohormone (preprohepcidin) which undergoes sequential cleavages to form the active, mature hormone. The first cleavage by signalpeptidase removes the 24-amino acid N-terminal signalpeptide, creating a 60-amino acid prohepcidin.Furin-like convertase[7] andα-1 antitrypsin[8] then cleave prohepcidin to remove a 35-amino acid proregion, resulting in the 25-amino acid mature, bioactive hepcidin. There are also shorterisoforms of hepcidin, with 20 and 22 amino acids, which have minimal iron regulatory activity. Only the 9N-terminal amino acids are essential for hepcidin's biological activity, specifically its ability to bind toferroportin and regulate iron metabolism.
Structurally, hepcidin is a tightly folded polypeptide with 32% beta-sheet character and a hairpin tertiary structure stabilized by fourdisulfide bonds among eightcystein residues (crucial structure). Hepcidin's structure has been elucidated through solution NMR,[9] revealing that it interconverts between two conformations at different temperatures. X-ray analysis of a co-crystal with Fab confirmed a structure similar to the high-temperature NMR structure.[10]
Hepcidin is a regulator of iron metabolism. It inhibits iron transport by binding to the iron export channelferroportin which is located in the basolateral plasma membrane of gutenterocytes and the plasma membrane ofreticuloendothelial cells (macrophages), ultimately resulting in ferroportin breakdown inlysosomes.[11][12] It has been shown that hepcidin is able to bind to the central cavity of ferroportin, thus occluding iron export from the cell. This suggests that hepcidin is able to regulate iron export independently of ferroportinendocytosis andubiquitination, and is thus quickly inducible and reversible.[13][14]
In enterocytes, this prevents iron transmission into thehepatic portal system, thereby reducing dietary iron absorption. In macrophages, ferroportin inhibition causes iron be to stored within the cell. Increased hepcidin activity is partially responsible for reduced iron availability seen in anemia of chronic inflammation, such askidney failure; this may explain why patients with end stage kidney failure may not respond to oral iron replacement.[15]
Any one of several mutations in hepcidin will result injuvenile hemochromatosis. The majority of juvenile hemochromatosis cases are caused by mutations inhemojuvelin.[16] Mutations inTMPRSS6 can cause anemia through dysregulation of hepcidin.[17]
Hepcidin has strongantimicrobial activity againstEscherichia coli strain ML35P andNeisseria cinerea and weaker antimicrobial activity againstStaphylococcus epidermidis,Staphylococcus aureus andStreptococcus agalactiae. It is also active against the fungusCandida albicans, but has no activity againstPseudomonas aeruginosa.[18]
Hepcidin creation (synthesis) andsecretion by the liver is controlled by iron stores,inflammation (hepcidin is anacute phase reactant),hypoxia, and production of red blood cells (erythropoiesis).[19] In response to large iron stores, production ofbone morphogenic protein (BMP) is induced, which binds to receptors onhepatocytes and induces hepcidin expression via theSMAD pathway.[20] Inflammation causes an increase in hepcidin production by releasing the signaling moleculeinterleukin-6 (IL-6), which binds to a receptor and upregulates the HAMP gene via theJAK/STAT pathway.[20] Hypoxia negatively regulates hepcidin production via production the transcription factorhypoxia-inducible factor (HIF), which under normal conditions is degraded byvon Hippel-Lindau (VHL) and prolyl dehydrogenase (PHD). However, when hypoxia is induced, PHD is inactivated, thus allowing HIF to down-regulate hepcidin production. Erythropoiesis decreases hepcidin production via production oferythropoietin (EPO), which has been shown to down-regulate hepcidin production.[20]
Severe anemia is associated with low hepcidin levels, even in the presence of inflammation.[21]Erythroferrone, produced in red blood cells (erythroblasts), has been identified as inhibiting hepcidin, thus providing more iron for hemoglobin synthesis in situations such as stress erythropoiesis.[22][23]
Vitamin D has been shown to decrease hepcidin, both in cell models looking at transcription and when given in large doses to human volunteers. Optimal function of hepcidin may require adequate levels of vitamin D in the blood.[24]
Hepcidin was initially reported and named in January 1998,[18] after it was observed that it was produced in the liver and appeared to have bactericidal (bacteria-killing) properties. Detailed descriptions were published in 2000–2001.[25][26][27] Although it is primarily synthesized in the liver, smaller amounts are synthesized in other tissues such asfat cells.[28]
Hepcidin was first discovered inhumanurine andblood serum.[29] Soon after this discovery, researchers discovered that hepcidin production inmice increases in conditions of iron overload as well as inflammation.Genetically modified mice engineered to overexpress hepcidin died shortly after birth with severe iron deficiency, again suggesting that hepcidin plays a central and not redundant role in iron regulation.
The first piece of evidence that linked hepcidin to the clinical condition known as theanemia of inflammation came from the lab ofNancy Andrews in Boston, when researchers looked at tissue from two patients with livertumors with a severemicrocytic anemia that did not respond toiron supplements. The tumor tissue appeared to be overproducing hepcidin, and contained large quantities of hepcidinmRNA. Removing the tumors surgically cured the anemia.[citation needed]
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 toiron deficiency andiron deficiency anemia. 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 these cases,parenteral iron treatment would be appropriate. Studies have found that measuring hepcidin would help establish the optimal treatment for a patient,[30] but as this is not widely available,C-reactive protein (CRP) is used as a surrogate marker.
Chronic alcohol consumption can lead to excess iron accumulation in the liver, which may contribute to the development ofalcoholic liver disease. Chronic alcohol use may increase iron accumulation by inhibiting hepcidingene expression. The main mechanisms appear to be increasingoxidative stress through its metaboliteacetaldehyde, and by inhibiting the release ofinterleukin 6 (IL-6) frommacrophages; each of these actions reduce the expression and DNA-binding activity of thetranscription factorC/EBPα, which would otherwise stimulate hepcidin expression.[31]
Beta thalassemia, one of the most commoncongenitalanemias, arises from partial or complete failure to synthesizebeta-globin, a component ofhemoglobin. Excessive iron absorption is one of the main features of beta thalassemia and can lead to severe morbidity and mortality. The serial analyses of beta thalassemic mice indicate that hemoglobin levels decrease over time, while the concentration of iron in theliver,spleen, andkidneys increases significantly. The overload of iron is associated with low levels of hepcidin. Patients with beta thalassemia also have low hepcidin levels. The observations led researchers to hypothesize that more iron is absorbed in beta thalassemia than is required forerythropoiesis. Increasing expression of hepcidin in beta thalassemic mice limits iron overload, and also decreases formation of insolublemembrane-bound globins and reactive oxygen species, and improves anemia.[32] Mice with increased hepcidin expression also demonstrated an increase in the lifespan of theirred cells, reversal of ineffective erythropoiesis andsplenomegaly, and an increase in total hemoglobin levels. From these data, researchers suggested thattherapeutics to increase hepcidin levels or act as hepcidinagonists could help treat the abnormal iron absorption in individuals with beta thalassemia and related disorders.[33] In later studies with mice,[34]erythroferrone has been suggested to be the factor that is responsible for the hepcidin suppression. Correcting hepcidin and iron levels in these mice did not improve their anemia.[34]
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