Hepcidin

Source: Wikipedia, the free encyclopedia.
"HAMP" redirects here. For other uses, see HAMP (disambiguation).
HAMP
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000105697

n/a

UniProt

P81172

n/a

RefSeq (mRNA)

NM_021175

n/a

RefSeq (protein)

NP_066998

n/a

Location (UCSC)Chr 19: 35.28 – 35.29 Mbn/a
PubMed search[2]n/a
Wikidata
View/Edit Human
Hepcidin
SCOP2
1m4f / SCOPe / SUPFAM
OPM superfamily153
OPM protein1m4e
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
Chr. 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.[4]

During conditions in which the hepcidin level is abnormally high, such as

hemochromatosis, iron overload occurs due to increased ferroportin
mediated iron efflux from storage and increased gut iron absorption.

Structure

Hepcidin exists as a

prohormone convertase furin.[5] This conversion may be regulated by alpha-1 antitrypsin.[6]

Hepcidin is a tightly folded polypeptide with 32%

co-crystal with Fab revealed a structure similar to the high-temperature NMR structure.[7]

Function

Further information: Human iron metabolism
Diagram showing how hepcidin controls ferroportin (FPN) 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

enterocytes, this prevents iron transmission into the hepatic portal system, thereby reducing dietary iron absorption. In macrophages, ferroportin inhibition causes iron sequestration within the cell. Increased hepcidin activity is partially responsible for reduced iron availability seen in anemia of chronic inflammation, such as kidney failure and that may explain why patient with end stage renal failure may not respond to oral iron replacement.[12]

Any one of several mutations in hepcidin result in juvenile hemochromatosis. The majority of juvenile hemochromatosis cases are due to mutations in hemojuvelin.[13] Mutations in TMPRSS6 can cause anemia through dysregulation of hepcidin.[14]

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.[15]

Regulation

Hepcidin synthesis and secretion by the liver is controlled by iron stores,

hypoxia, and erythropoiesis.[16] 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.[17] 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.[17] 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). When hypoxia is induced, however, 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.[17]

Severe anaemia is associated with low hepcidin levels, even in the presence of inflammation.[18] Erythroferrone, produced in erythroblasts, has been identified as inhibiting hepcidin and so providing more iron for hemoglobin synthesis in situations such as stress erythropoiesis.[19][20]

Vitamin D has been shown to decrease hepcidin, in cell models looking at transcription and when given in large doses to human volunteers. Optimal function of hepcidin may be predicated upon the adequate presence of vitamin D in the blood.[21]

History

The peptide was initially reported in January 1998 by Valore,E., Park,C. and Ganz,T. in the SWISS-PROT database as entry P81172 and named hepcidin[15] after it was observed that it was produced in the liver ("hep-") and appeared to have bactericidal properties ("-cide" for "killing"). Detailed descriptions were published in 2000-2001.[22][23][24] Although it is primarily synthesized in the liver, smaller amounts are synthesised in other tissues such as fat cells.[25]

Hepcidin was first discovered in

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]

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 (FPN)

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

parenteral iron treatment would be appropriate. Studies have found that measuring hepcidin would be of benefit to establish optimal treatment,[27] although as this is not widely available, C-reactive protein
(CRP) is used as a surrogate marker.

agonists could help treat the abnormal iron absorption in individuals with β-thalassemia and related disorders.[29] In later studies in mice,[30] 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.[30]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000105697 - Ensembl, May 2017
  2. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ^
    PMID 12138110
    .
  4. PMID 12663437
    .
  5. PMID 17905609
    .
  6. S2CID 28974553
    .
  7. PMID 19553669
    .
  8. PMID 16450011
    .
  9. PMID 24994858
    .
  10. PMID 29237594
    .
  11. PMID 34204327
    .
  12. PMID 19212416
    .
  13. PMID 24860505
    .
  14. ISBN 978-1-4649-8960-5
    .
  15. ^ a b "Hepcidin P81172". UniProt. December 15, 1998.
  16. PMID 23722909
    .
  17. ^
    PMID 26182354
    .
  18. S2CID 237454351
    .
  19. ^ Koury MJ. "Erythroferrone: A Missing Link in Iron Regulation". The Hematologist. American Society of Hematology. Archived from the original on 28 January 2019. Retrieved 26 August 2015.
  20. PMID 24880340
    .
  21. PMID 24204002
    .
  22. S2CID 9161764
    .
  23. PMID 11113132
    .
  24. PMID 11113131
    .
  25. PMID 16952548
    .
  26. PMID 18166790
    .
  27. S2CID 42656065
    .
  28. PMID 21099112
    .
  29. PMID 21989113
    .
  30. ^
    PMID 26494918
    .

Further reading

External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Hepcidin&oldid=1209720609"