Details for: HAMP

Gene ID: 57817

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: HAMP

Ensembl ID: ENSG00000105697

Description: hepcidin antimicrobial peptide

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

  • Antimicrobial humoral immune response mediated by antimicrobial peptide
    (GO:0061844)
  • Cell surface receptor signaling pathway via jak-stat
    (GO:0007259)
  • Copper ion binding
    (GO:0005507)
  • Defense response to bacterium
    (GO:0042742)
  • Defense response to fungus
    (GO:0050832)
  • Defense response to gram-negative bacterium
    (GO:0050829)
  • Defense response to gram-positive bacterium
    (GO:0050830)
  • Establishment of localization in cell
    (GO:0051649)
  • Extracellular region
    (GO:0005576)
  • Extracellular space
    (GO:0005615)
  • Hormone activity
    (GO:0005179)
  • Immune response
    (GO:0006955)
  • Inflammatory response
    (GO:0006954)
  • Intracellular iron ion homeostasis
    (GO:0006879)
  • Iron ion transmembrane transport
    (GO:0034755)
  • Iron ion transmembrane transporter inhibitor activity
    (GO:0097690)
  • Killing of cells of another organism
    (GO:0031640)
  • Macrophage activation
    (GO:0042116)
  • Multicellular organismal-level iron ion homeostasis
    (GO:0060586)
  • Myeloid cell homeostasis
    (GO:0002262)
  • Negative regulation of bone resorption
    (GO:0045779)
  • Negative regulation of inflammatory response
    (GO:0050728)
  • Negative regulation of intestinal absorption
    (GO:1904479)
  • Negative regulation of ion transmembrane transporter activity
    (GO:0032413)
  • Negative regulation of iron export across plasma membrane
    (GO:1904039)
  • Negative regulation of iron ion transmembrane transport
    (GO:0034760)
  • Negative regulation of iron ion transmembrane transporter activity
    (GO:1904255)
  • Negative regulation of transcription by rna polymerase ii
    (GO:0000122)
  • Nucleus
    (GO:0005634)
  • Positive regulation of macrophage activation
    (GO:0043032)
  • Positive regulation of proteasomal ubiquitin-dependent protein catabolic process
    (GO:0032436)
  • Positive regulation of protein polyubiquitination
    (GO:1902916)
  • Positive regulation of receptor catabolic process
    (GO:2000646)
  • Positive regulation of receptor internalization
    (GO:0002092)
  • Positive regulation of transcription by rna polymerase ii
    (GO:0045944)
  • Protein catabolic process
    (GO:0030163)
  • Response to iron ion
    (GO:0010039)
  • Signaling receptor binding
    (GO:0005102)
  • Signal transduction
    (GO:0007165)
  • Transcription by rna polymerase ii
    (GO:0006366)
  • Transporter regulator activity
    (GO:0141108)

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • midzonal region hepatocyte CL0019028
    CSI 13.32
    rCSI 31.27%
    PRS 88.82
  • cardiac muscle cell CL0000746
    CSI 12.38
    rCSI 17.77%
    PRS 83.67
  • hepatocyte CL0000182
    CSI 11.96
    rCSI 21.4%
    PRS 89.68
  • inflammatory macrophage CL0000863
    CSI 11.56
    rCSI 19.76%
    PRS 97.49
  • central nervous system macrophage CL0000878
    CSI 11.08
    rCSI 36.72%
    PRS 93.01
  • centrilobular region hepatocyte CL0019029
    CSI 10.47
    rCSI 27.32%
    PRS 87.22
  • monocyte CL0000576
    CSI 6.59
    rCSI 11.91%
    PRS 92.25
  • periportal region hepatocyte CL0019026
    CSI 6.47
    rCSI 25.18%
    PRS 88.07
  • macrophage CL0000235
    CSI 3.77
    rCSI 6.86%
    PRS 91.69
  • Schwann cell CL0002573
    CSI 3.32
    rCSI 9.43%
    PRS 87.81
  • hepatic stellate cell CL0000632
    CSI 3.06
    rCSI 11.45%
    PRS 86.95
  • microglial cell CL0000129
    CSI 2.98
    rCSI 12%
    PRS 89.63
  • Kupffer cell CL0000091
    CSI 2.79
    rCSI 6.38%
    PRS 92.05
  • elicited macrophage CL0000861
    CSI 2.73
    rCSI 2.5%
    PRS 95.06
  • intrahepatic cholangiocyte CL0002538
    CSI 2.09
    rCSI 5.01%
    PRS 91.06
  • regular atrial cardiac myocyte CL0002129
    CSI 2.05
    rCSI 6.6%
    PRS 87.83
  • pancreatic acinar cell CL0002064
    CSI 1.86
    rCSI 2.47%
    PRS 93.69
  • endothelial cell of pericentral hepatic sinusoid CL0019022
    CSI 1.66
    rCSI 5.11%
    PRS 92.62
  • cholangiocyte CL1000488
    CSI 1.06
    rCSI 6.36%
    PRS 90.34

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [HAMP](/details-gene/57817) encodes hepcidin, a peptide hormone and antimicrobial peptide that functions as the master regulator of systemic iron homeostasis. Primarily synthesized in the liver, hepcidin controls iron absorption from the intestine and iron release from macrophages by inducing the degradation of the iron exporter ferroportin [[Link](https://pubmed.ncbi.nlm.nih.gov/22306005/)]. Its expression is tightly regulated by iron levels, inflammation, and erythropoietic demand. The **Overall** expression profile highlights its profound significance in various types of [hepatocytes](/details-cell/CL0000182), confirming its role as a liver-derived hormone. Additionally, its high significance in [inflammatory macrophages](/details-cell/CL0000863) and [cardiac muscle cells](/details-cell/CL0000746) points toward critical roles in immune response and organ-specific iron handling. Dysregulation of [HAMP](/details-gene/57817) is central to the pathophysiology of both iron overload disorders, such as hereditary hemochromatosis, and iron-deficiency anemias, particularly the anemia of inflammation [[Link](https://pubmed.ncbi.nlm.nih.gov/15124018/)] [[Link](https://doi.org/10.1093/hmg/ddg225)]. ## Cellular Roles and Expression Landscape The expression landscape of [HAMP](/details-gene/57817) underscores its dual function in systemic metabolism and local immune responses. **Overall**, the gene shows the highest significance in liver parenchymal cells, including [midzonal region hepatocytes](/details-cell/CL0019028) (CSI: 13.32), [hepatocytes](/details-cell/CL0000182) (CSI: 11.96), and [centrilobular region hepatocytes](/details-cell/CL0019029) (CSI: 10.47). This is consistent with the liver's role as the central organ for hepcidin production to regulate whole-body iron balance. A second major functional context for [HAMP](/details-gene/57817) is the myeloid lineage of the immune system. The gene is highly significant in [inflammatory macrophages](/details-cell/CL0000863) (CSI: 11.56), [central nervous system macrophages](/details-cell/CL0000878) (CSI: 11.08), and [monocytes](/details-cell/CL0000576) (CSI: 6.59). This suggests that in addition to its systemic endocrine function, hepcidin may act locally in a paracrine or autocrine manner during inflammation to sequester iron, a key component of nutritional immunity aimed at restricting pathogen growth. Notably, [HAMP](/details-gene/57817) also demonstrates a high significance score in [cardiac muscle cells](/details-cell/CL0000746) (CSI: 12.38), suggesting a potential, less-characterized role in cardiac iron metabolism. Its moderate significance in other liver-resident cells like [hepatic stellate cells](/details-cell/CL0000632) and [Kupffer cells](/details-cell/CL0000091) further reinforces its integral role within the liver microenvironment. ## Pathways and Molecular Function The functions of [HAMP](/details-gene/57817) are primarily centered on iron metabolism and host defense, as reflected in its associated gene ontology terms. Its principal molecular function is as an [iron ion transmembrane transporter inhibitor](/details-cell/GO:0097690), acting as a hormone ([GO:0005179](https://www.ebi.ac.uk/QuickGO/term/GO:0005179)) to negatively regulate iron export. This is achieved by binding to the iron transporter ferroportin, leading to its internalization and proteasomal degradation, a process involving ubiquitination [[Link](https://doi.org/10.1016/j.cmet.2012.03.018/)] [[Link](https://doi.org/10.1038/s41586-020-2668-z)]. This activity is central to the biological processes of [multicellular organismal-level iron ion homeostasis](/details-cell/GO:0060586) and [intracellular iron ion homeostasis](/details-cell/GO:0006879). Consistent with its high significance in macrophages, [HAMP](/details-gene/57817) is deeply involved in the [immune response](/details-cell/GO:0006955) and [inflammatory response](/details-cell/GO:0006954). Its production is induced by inflammatory cytokines like IL-6, linking systemic inflammation to iron sequestration [[Link](https://doi.org/10.1172/jci20945)]. This connects to its roles in [macrophage activation](/details-cell/GO:0042116) and direct antimicrobial functions, including [defense response to bacterium](/details-cell/GO:0042742) and [fungus](/details-cell/GO:0050832), as hepcidin was initially discovered as a liver-expressed antimicrobial peptide (LEAP-1) [[Link](https://doi.org/10.1016/s0014-5793(00)01920-7/)]. The protein is secreted into the [extracellular space](/details-cell/GO:0005615), where it exerts its endocrine and paracrine effects. ## Research Directions The expression profile of [HAMP](/details-gene/57817) across hepatic, myeloid, and cardiac cells opens several avenues for future investigation into its context-specific roles. The distinction between systemic production by hepatocytes and local production by macrophages, particularly during inflammation, warrants further study to dissect its endocrine versus paracrine signaling functions. Based on the available data, several testable hypotheses can be proposed: 1. **Hypothesis:** The high significance of [HAMP](/details-gene/57817) in [cardiac muscle cells](/details-cell/CL0000746) indicates an intrinsic cardioprotective mechanism where locally produced hepcidin regulates cardiomyocyte iron content to mitigate oxidative stress during pathological conditions like ischemia or iron overload cardiomyopathy. 2. **Hypothesis:** Autocrine production of hepcidin by [central nervous system macrophages](/details-cell/CL0000878) and [microglial cells](/details-cell/CL0000129) is a primary driver of iron sequestration within the brain during neuroinflammation, contributing to neuronal damage in diseases such as Parkinson's disease or multiple sclerosis by limiting iron availability for essential cellular processes. **Experimental Approach:** To test the first hypothesis regarding the role of [HAMP](/details-gene/57817) in cardiomyocytes, a series of experiments could be conducted. A cardiomyocyte-specific knockout of [HAMP](/details-gene/57817) could be generated in a mouse model using the Cre-lox system with a Cre driver under the control of the alpha-myosin heavy chain promoter. These mice, alongside wild-type littermates, could be subjected to models of cardiac stress, such as angiotensin II infusion to induce hypertrophy or surgical ligation of the left anterior descending artery to induce myocardial infarction. The impact of local hepcidin deficiency could be assessed by measuring cardiac function (echocardiography), infarct size, fibrosis, cellular iron content (Perls' stain, ICP-MS), and markers of oxidative stress. **Therapeutic Potential:** [HAMP](/details-gene/57817) and its pathway represent a highly attractive therapeutic target for a range of iron disorders. - **Inhibition:** For conditions of pathologically high hepcidin, such as anemia of inflammation, strategies to inhibit hepcidin action are in advanced development. These include anti-hepcidin antibodies, antisense oligonucleotides targeting [HAMP](/details-gene/57817) mRNA, or inhibitors of the upstream BMP-SMAD signaling pathway. The goal of such inhibition is to increase ferroportin stability and restore iron efflux, thereby improving iron availability for red blood cell production. - **Activation/Agonism:** Conversely, in iron overload diseases like hereditary hemochromatosis, which are caused by hepcidin deficiency, therapeutic strategies focus on hepcidin replacement or mimicking its activity. Hepcidin agonists (mimetics) are being developed to bind and induce the degradation of ferroportin, thus reducing dietary iron absorption and sequestering excess iron in macrophages. Given that hepcidin is a secreted peptide hormone, both inhibitory and agonistic approaches can effectively target it in the extracellular space.

Genular Protein ID: 3949883863

Symbol: HEPC_HUMAN

Name: Liver-expressed antimicrobial peptide 1

UniProtKB Accession Codes:

P81172 Q1HE14 Q9BY68

Database IDs:

ABCD 1 AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CTD 1 ChEMBL 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 1 EMBL 7 EMDB 1 Ensembl 2 EvolutionaryTrace 1 GO 30 GeneCards 1 GeneReviews 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 1 KEGG 1 MANE-Select 1 MIM 3 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 2 OrthoDB 1 PANTHER 2 PDB 6 PDBsum 6 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 RefSeq 1 SIGNOR 1 SMR 1 STRING 1 SignaLink 1 TCDB 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 11113131

Title: Hepcidin: a urinary antimicrobial peptide synthesized in the liver.

PubMed ID: 11113131

DOI: 10.1074/jbc.m008922200

PubMed ID: 11034317

Title: LEAP-1, a novel highly disulfide-bonded human peptide exhibits antimicrobial activity.

PubMed ID: 11034317

DOI: 10.1016/s0014-5793(00)01920-7

PubMed ID: 12975309

Title: The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment.

PubMed ID: 12975309

DOI: 10.1101/gr.1293003

PubMed ID: 15057824

Title: The DNA sequence and biology of human chromosome 19.

PubMed ID: 15057824

DOI: 10.1038/nature02399

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 12010514

Title: Chemical synthesis of beta-defensins and LEAP-1/hepcidin.

PubMed ID: 12010514

DOI: 10.1034/j.1399-3011.2002.00980.x

PubMed ID: 15124018

Title: IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin.

PubMed ID: 15124018

DOI: 10.1172/jci20945

PubMed ID: 22306005

Title: Hepcidin and iron homeostasis.

PubMed ID: 22306005

DOI: 10.1016/j.bbamcr.2012.01.014

PubMed ID: 22682227

Title: Hepcidin-induced endocytosis of ferroportin is dependent on ferroportin ubiquitination.

PubMed ID: 22682227

DOI: 10.1016/j.cmet.2012.03.018

PubMed ID: 29237594

Title: Structure-function analysis of ferroportin defines the binding site and an alternative mechanism of action of hepcidin.

PubMed ID: 29237594

DOI: 10.1182/blood-2017-05-786590

PubMed ID: 12138110

Title: The solution structure of human hepcidin, a peptide hormone with antimicrobial activity that is involved in iron uptake and hereditary hemochromatosis.

PubMed ID: 12138110

DOI: 10.1074/jbc.m205305200

PubMed ID: 19553669

Title: Hepcidin revisited, disulfide connectivity, dynamics, and structure.

PubMed ID: 19553669

DOI: 10.1074/jbc.m109.017764

PubMed ID: 32814342

Title: Structure of hepcidin-bound ferroportin reveals iron homeostatic mechanisms.

PubMed ID: 32814342

DOI: 10.1038/s41586-020-2668-z

PubMed ID: 14633868

Title: Identification of new mutations of the HFE, hepcidin, and transferrin receptor 2 genes by denaturing HPLC analysis of individuals with biochemical indications of iron overload.

PubMed ID: 14633868

DOI: 10.1373/clinchem.2003.023440

PubMed ID: 12915468

Title: Digenic inheritance of mutations in HAMP and HFE results in different types of haemochromatosis.

PubMed ID: 12915468

DOI: 10.1093/hmg/ddg225

PubMed ID: 14630809

Title: Screening hepcidin for mutations in juvenile hemochromatosis: identification of a new mutation (C70R).

PubMed ID: 14630809

DOI: 10.1182/blood-2003-10-3390

PubMed ID: 14670915

Title: HAMP as a modifier gene that increases the phenotypic expression of the HFE pC282Y homozygous genotype.

PubMed ID: 14670915

DOI: 10.1182/blood-2003-10-3366

PubMed ID: 15099344

Title: A homozygous HAMP mutation in a multiply consanguineous family with pseudo-dominant juvenile hemochromatosis.

PubMed ID: 15099344

DOI: 10.1111/j.0009-9163.2004.00254.x

Sequence Information:

  • Length: 84
  • Mass: 9408
  • Checksum: 5F8DCA23D19D29F7
  • Sequence:
    • MALSSQIWAA CLLLLLLLAS LTSGSVFPQQ TGQLAELQPQ DRAGARASWM PMFQRRRRRD 
THFPICIFCC GCCHRSKCGM CCKT