HAMP Gene (Hepcidin)
<div class="infobox">
<table>
<tr><td><strong>Symbol</strong></td><td>HAMP</td></tr>
<tr><td><strong>Full Name</strong></td><td>Hepcidin Antimicrobial Peptide</td></tr>
<tr><td><strong>Protein</strong></td><td>[Hepcidin](/entities/hepcidin-protein)</td></tr>
<tr><td><strong>Chromosome</strong></td><td>19q13.1</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>57817</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>P81172</td></tr>
<tr><td><strong>Aliases</strong></td><td>HEPC, HEPCIDIN, HFE2B, LEAP1, PLTR</td></tr>
</table>
</div>
Overview
[HAMP](/entities/hamp) encodes hepcidin, the master regulator of systemic iron homeostasis and a key antimicrobial peptide.[@ganz2003] Hepcidin controls iron absorption and distribution by binding to and inducing the internalization of ferroportin, the sole cellular iron exporter.[@nemeth2004] Dysregulation of the hepcidin-ferroportin axis contributes to brain iron accumulation in neurodegenerative diseases.[@ward2014]
Structure and Expression
The HAMP gene spans approximately 2.6 kb on chromosome 19q13.1 and contains 3 exons encoding an 84-amino acid prepropeptide that is processed to the mature 25-amino acid hepcidin peptide.[@pigeon2001] Hepcidin is predominantly expressed in:
- Hepatocytes: Primary source of circulating hepcidin
- Macrophages: Local regulation of iron export
- Brain cells: [Neurons](/entities/neurons) and [astrocytes](/entities/astrocytes) produce hepcidin for local iron regulation[@zanninelli2002]
Normal Function
...HAMP Gene (Hepcidin)
<div class="infobox">
<table>
<tr><td><strong>Symbol</strong></td><td>HAMP</td></tr>
<tr><td><strong>Full Name</strong></td><td>Hepcidin Antimicrobial Peptide</td></tr>
<tr><td><strong>Protein</strong></td><td>[Hepcidin](/entities/hepcidin-protein)</td></tr>
<tr><td><strong>Chromosome</strong></td><td>19q13.1</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>57817</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>P81172</td></tr>
<tr><td><strong>Aliases</strong></td><td>HEPC, HEPCIDIN, HFE2B, LEAP1, PLTR</td></tr>
</table>
</div>
Overview
[HAMP](/entities/hamp) encodes hepcidin, the master regulator of systemic iron homeostasis and a key antimicrobial peptide.[@ganz2003] Hepcidin controls iron absorption and distribution by binding to and inducing the internalization of ferroportin, the sole cellular iron exporter.[@nemeth2004] Dysregulation of the hepcidin-ferroportin axis contributes to brain iron accumulation in neurodegenerative diseases.[@ward2014]
Structure and Expression
The HAMP gene spans approximately 2.6 kb on chromosome 19q13.1 and contains 3 exons encoding an 84-amino acid prepropeptide that is processed to the mature 25-amino acid hepcidin peptide.[@pigeon2001] Hepcidin is predominantly expressed in:
- Hepatocytes: Primary source of circulating hepcidin
- Macrophages: Local regulation of iron export
- Brain cells: [Neurons](/entities/neurons) and [astrocytes](/entities/astrocytes) produce hepcidin for local iron regulation[@zanninelli2002]
Normal Function
Hepcidin serves as the systemic iron regulatory hormone with the following functions:
Iron Export Inhibition: Binds ferroportin and induces internalization and degradation
Iron Homeostasis: Maintains appropriate serum iron levels
Antimicrobial Activity: Sequesters iron from pathogens as part of innate immunity
Inflammatory Response: Upregulated by interleukin-6 (IL-6) during inflammation[@nemeth2004a]Role in Neurodegeneration
Neuroinflammation and Iron Dysregulation
Chronic neuroinflammation in neurodegenerative diseases upregulates hepcidin expression via IL-6 signaling, leading to ferroportin suppression and neuronal iron retention.[@urrutia2013] This creates a vicious cycle where iron accumulation promotes oxidative stress, which further drives inflammation.
Parkinson's Disease
In [Parkinson's disease](/diseases/parkinsons-disease), elevated hepcidin expression has been observed in the substantia nigra.[@wang2007] This contributes to iron accumulation in dopaminergic neurons, promoting oxidative damage and [alpha-synuclein](/proteins/alpha-synuclein) aggregation. Hepcidin levels correlate with disease severity and may serve as a biomarker.
Alzheimer's Disease
[Alzheimer's disease](/diseases/alzheimers-disease) patients show altered cerebrospinal fluid hepcidin levels and increased brain hepcidin expression.[@raha2013] Hepcidin-mediated suppression of ferroportin may contribute to iron accumulation in amyloid plaques and neurofibrillary tangles.
Amyotrophic Lateral Sclerosis
In [ALS](/diseases/amyotrophic-lateral-sclerosis), elevated serum hepcidin correlates with disease progression rate and reduced survival.[@goodall2008] Iron accumulation in motor neurons may be driven by hepcidin upregulation secondary to systemic inflammation.
Molecular Mechanisms
Hepcidin-Ferroportin Interaction
Hepcidin binds to ferroportin at a specific extracellular loop, inducing ubiquitination, internalization via clathrin-coated pits, and lysosomal degradation.[@qiao2012] Each hepcidin molecule inactivates one ferroportin molecule, blocking iron export for 24-48 hours.
Ferroptosis
Hepcidin-mediated ferroportin suppression leads to intracellular iron accumulation, promoting [ferroptosis](/entities/ferroptosis)—an iron-dependent form of regulated cell death characterized by lipid peroxidation.[@stockwell2017] Ferroptosis has been implicated in neuronal death in PD, AD, and ALS.
Regulation by Iron and Inflammation
Hepcidin expression is regulated by:
- Iron status: High serum iron increases hepcidin via BMP-SMAD signaling
- Inflammation: IL-6 activates JAK-STAT signaling to induce hepcidin
- Hypoxia: HIF suppresses hepcidin to increase iron availability
- Erythropoiesis: Erythroferrone from developing red blood cells suppresses hepcidin[@kautz2014]
Therapeutic Implications
Hepcidin Antagonists: Antibodies or small molecules blocking hepcidin-ferroportin interaction
Anti-inflammatory Agents: Reducing IL-6-driven hepcidin upregulation
Iron Chelation: Deferiprone and deferoxamine reduce brain iron burden
Ferroptosis Inhibitors: Ferrostatin-1 and liproxstatin-1 prevent iron-dependent cell death[@devos2014]Key Interactions
| Protein | Relationship | Function |
|---------|--------------|----------|
| [Ferroportin](/entities/fpn1) | Target | Hepcidin induces internalization |
| IL-6 | Inducer | Activates JAK-STAT signaling |
| BMP6 | Inducer | Activates SMAD signaling |
| HFE | Regulator | Mutations alter hepcidin expression |
| TfR2 | Regulator | Senses iron status |
See Also
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
External Links
- [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
- [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)
- [Allen Human Brain Atlas](https://brain-map.org/)
References
[Ganz T, Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation (2003)](https://pubmed.ncbi.nlm.nih.gov/14630868/)
[Nemeth E, Tuttle MS, Powelson J, et al, Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization (2004)](https://doi.org/10.1126/science.1104742)
[Ward RJ, Zucca FA, Duyn JH, Crichton RR, Zecca L, The role of iron in brain ageing and neurodegenerative disorders (2014)](https://pubmed.ncbi.nlm.nih.gov/24789079/)
[Pigeon C, Ilyin G, Courselaud B, et al, A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload (2001)](https://pubmed.ncbi.nlm.nih.gov/11278534/)
[Zanninelli G, Loreal O, Brissot P, et al, The central role of the liver in iron homeostasis and hemochromatosis (2002)](https://pubmed.ncbi.nlm.nih.gov/11341865/)
[Nemeth E, Rivera S, Gabayan V, et al, IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin (2004)](https://doi.org/10.1172/JCI20945)
[Urrutia P, Aguirre P, Esparza A, et al, Inflammation alters the expression of DMT1, FPN1 and hepcidin, and it causes iron accumulation in central nervous system cells (2013)](https://pubmed.ncbi.nlm.nih.gov/23506787/)
[Wang J, Jiang H, Xie JX, Ferroportin1 and hepcidin expression in rat midbrain and the effect of iron on hepcidin expression (2007)](https://pubmed.ncbi.nlm.nih.gov/17724598/)
[Raha AA, Vaishnav RA, Friedland RP, et al, The systemic iron-regulatory proteins hepcidin and ferroportin are reduced in the brain in Alzheimer's disease (2013)](https://pubmed.ncbi.nlm.nih.gov/23860225/)
[Goodall EF, Haque MS, Morrison KE, Increased serum ferritin levels in amyotrophic lateral sclerosis (ALS) patients (2008)](https://pubmed.ncbi.nlm.nih.gov/18379194/)
[Qiao B, Sugianto P, Schmidt PJ, et al, Hepcidin-induced endocytosis of ferroportin is dependent on ferroportin ubiquitination (2012)](https://doi.org/10.1007/s00109-011-0833-5)
[Stockwell BR, Friedmann Angeli JP, Bayir H, et al, Ferroptosis: A Regulated Cell Death Nexus Connecting Metabolism, Redox Biology, and Disease (2017)](https://doi.org/10.1016/j.cell.2017.09.021)
[Kautz L, Jung G, Valore EV, et al, Identification of erythroferrone as an erythroid regulator of iron metabolism (2014)](https://doi.org/10.1038/ng.2570)
[Devos D, Moreau C, Devedjian JC, et al, Targeting chelatable iron as a therapeutic modality in Parkinson's disease (2014)](https://pubmed.ncbi.nlm.nih.gov/24864761/)