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Hepcidin

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(Redirected from HAMP)
"HAMP" redirects here. For other uses, see HAMP (disambiguation).
HAMP
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesHAMP, HEPC, HFE2B, LEAP1, PLTR, hepcidin antimicrobial peptide
External IDsOMIM: 606464; MGI: 2153530; HomoloGene: 81623; GeneCards: HAMP; OMA:HAMP - orthologs
Orthologs
SpeciesHumanMouse
Entrez

57817

66438

Ensembl

ENSG00000105697

ENSMUSG00000056978

UniProt

P81172

Q80T19

RefSeq (mRNA)

NM_021175

NM_183257

RefSeq (protein)

NP_066998

NP_899080

Location (UCSC)Chr 19: 35.28 – 35.29 MbChr 7: 30.62 – 30.62 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Hepcidin
Solution structure of hepcidin-25.[5]
Identifiers
SymbolHepcidin
PfamPF06446
InterProIPR010500
SCOP21m4f / SCOPe / SUPFAM
OPM superfamily153
OPM protein1m4e
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
hepcidin antimicrobial peptide
Identifiers
SymbolHAMP
NCBI gene57817
HGNC15598
OMIM606464
RefSeqNM_021175
UniProtP81172
Other data
LocusChr. 19 q13.1
Search for
StructuresSwiss-model
DomainsInterPro

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.[6]

During conditions 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 blood serum iron being available for developing red blood cells. When the hepcidin level is abnormally low, such as in hemochromatosis, iron overload occurs due to increased ferroportin mediated iron efflux from storage and increased gut iron absorption.

Structure

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Hepcidin is initially synthesized as an 84-amino acid preprohormone (preprohepcidin) which undergoes sequential cleavages to form the active, mature hormone. The first cleavage by signal peptidase removes the 24-amino acid N-terminal signal peptide, creating a 60-amino acid prohepcidin. Furin-like convertase[7] and α-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 shorter isoforms of hepcidin, with 20 and 22 amino acids, which have minimal iron regulatory activity. Only the 9 N-terminal amino acids are essential for hepcidin's biological activity, specifically its ability to bind to ferroportin and regulate iron metabolism.

Structurally, hepcidin is a tightly folded polypeptide with 32% beta-sheet character and a hairpin tertiary structure stabilized by four disulfide bonds among eight cystein 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]

Function

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Further information: Human iron metabolism
Diagram showing how hepcidin controls ferroportin levels, which in turn control entry of iron into the circulation

Hepcidin is a regulator of iron metabolism. It inhibits iron transport by binding to the iron export channel ferroportin which is located in the basolateral plasma membrane of gut enterocytes and the plasma membrane of reticuloendothelial cells (macrophages), ultimately resulting in ferroportin breakdown in lysosomes.[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 ferroportin endocytosis and ubiquitination, and is thus quickly inducible and reversible.[13][14]

In enterocytes, this prevents iron transmission into the hepatic 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 as kidney 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 in juvenile hemochromatosis. The majority of juvenile hemochromatosis cases are caused by mutations in hemojuvelin.[16] Mutations in TMPRSS6 can cause anemia through dysregulation of hepcidin.[17]

Hepcidin has strong antimicrobial activity against Escherichia coli strain ML35P and Neisseria cinerea and weaker antimicrobial activity against Staphylococcus epidermidis, Staphylococcus aureus and Streptococcus agalactiae. It is also active against the fungus Candida albicans, but has no activity against Pseudomonas aeruginosa.[18]

Regulation

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Hepcidin creation (synthesis) and secretion by the liver is controlled by iron stores, inflammation (hepcidin is an acute phase reactant), hypoxia, and production of red blood cells (erythropoiesis).[19] In response to large iron stores, production of bone morphogenic protein (BMP) is induced, which binds to receptors on hepatocytes and induces hepcidin expression via the SMAD pathway.[20] Inflammation causes an increase in hepcidin production by releasing the signaling molecule interleukin-6 (IL-6), which binds to a receptor and upregulates the HAMP gene via the JAK/STAT pathway.[20] Hypoxia negatively regulates hepcidin production via production the transcription factor hypoxia-inducible factor (HIF), which under normal conditions is degraded by von 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 of erythropoietin (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]

History

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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 as fat cells.[28]

Hepcidin was first discovered in human urine and blood serum.[29] Soon after this discovery, researchers discovered that hepcidin production in mice 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 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.[citation needed]

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

This image depicts the structure of Ferroportin with Hepcidin bound. The original image was modified to exclude the Fragment Antigen used to image the protein.
Hepcidin (blue) bound to the central cavity of ferroportin

Clinical significance

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There are many diseases where failure to adequately absorb iron contributes to iron deficiency and iron 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 of alcoholic liver disease. Chronic alcohol use may increase iron accumulation by inhibiting hepcidin gene expression. The main mechanisms appear to be increasing oxidative stress through its metabolite acetaldehyde, and by inhibiting the release of interleukin 6 (IL-6) from macrophages; each of these actions reduce the expression and DNA-binding activity of the transcription factor C/EBPα, which would otherwise stimulate hepcidin expression.[31]

Beta thalassemia, one of the most common congenital anemias, arises from partial or complete failure to synthesize beta-globin, a component of hemoglobin. 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 the liver, spleen, and kidneys 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 for erythropoiesis. Increasing expression of hepcidin in beta thalassemic mice limits iron overload, and also decreases formation of insoluble membrane-bound globins and reactive oxygen species, and improves anemia.[32] 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. From these data, researchers suggested that therapeutics to increase hepcidin levels or act as hepcidin agonists 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]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000105697 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000056978 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ PDB: 1M4F​; Hunter HN, Fulton DB, Ganz T, Vogel HJ (October 2002). "The solution structure of human hepcidin, a peptide hormone with antimicrobial activity that is involved in iron uptake and hereditary hemochromatosis". The Journal of Biological Chemistry. 277 (40): 37597–37603. doi:10.1074/jbc.M205305200. PMID 12138110.
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  7. ^ Valore EV, Ganz T (2008). "Posttranslational processing of hepcidin in human hepatocytes is mediated by the prohormone convertase furin". Blood Cells, Molecules & Diseases. 40 (1): 132–138. doi:10.1016/j.bcmd.2007.07.009. PMC 2211381. PMID 17905609.
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  10. ^ PDB: 3H0T​; Jordan JB, Poppe L, Haniu M, Arvedson T, Syed R, Li V, et al. (September 2009). "Hepcidin revisited, disulfide connectivity, dynamics, and structure". The Journal of Biological Chemistry. 284 (36): 24155–24167. doi:10.1074/jbc.M109.017764. PMC 2782009. PMID 19553669.
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  32. ^ Gardenghi S, Ramos P, Marongiu MF, Melchiori L, Breda L, Guy E, et al. (December 2010). "Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice". The Journal of Clinical Investigation. 120 (12): 4466–4477. doi:10.1172/JCI41717. PMC 2993583. PMID 21099112.
  33. ^ Kroot JJ, Tjalsma H, Fleming RE, Swinkels DW (December 2011). "Hepcidin in human iron disorders: diagnostic implications". Clinical Chemistry. 57 (12): 1650–1669. doi:10.1373/clinchem.2009.140053. hdl:2066/97956. PMID 21989113.
  34. ^ a b Moura IC, Hermine O (October 2015). "Erythroferrone: the missing link in β-thalassemia?". Blood. 126 (17): 1974–1975. doi:10.1182/blood-2015-09-665596. PMID 26494918.

Further reading

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