Affinage

HFE

Hereditary hemochromatosis protein · UniProt Q30201

Length
348 aa
Mass
40.1 kDa
Annotated
2026-06-10
100 papers in source corpus 25 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HFE is an MHC class I-like protein that functions as a hepatocyte iron sensor governing systemic iron homeostasis, and its disruption causes hereditary hemochromatosis through inappropriately low levels of the iron-regulatory hormone hepcidin (PMID:9482913, PMID:18316026, PMID:14673107). HFE binds the extracellular dimerization domain of transferrin receptor 1 (TfR1) using the helices that correspond to the MHC peptide-binding groove, occupying a site that overlaps the diferric-transferrin (Fe-Tf) binding site, so that HFE and Fe-Tf compete directly for each TfR1 chain without negative cooperativity (PMID:10638746, PMID:10556042, PMID:15056661). This competition reduces transferrin-mediated iron uptake and lowers the intracellular labile iron pool, activating iron-regulatory proteins (PMID:10572108, PMID:18393371). The sensing logic is that HFE induces hepcidin when displaced from TfR1: forcing constitutive HFE–TfR1 interaction lowers hepcidin and causes iron overload, while preventing it raises hepcidin, and hepatocyte TfR1's principal non-redundant role in iron homeostasis is to sequester HFE (PMID:18316026, PMID:36322932). Free HFE stabilizes the BMP type I receptor ALK3 by inhibiting its ubiquitination and proteasomal degradation, thereby increasing ALK3 surface levels and Smad1/5/8 phosphorylation, and this hepcidin induction is genetically dependent on the HJV-mediated BMP–Smad pathway (PMID:24904118, PMID:25609138, PMID:25608116); the C282Y and H63D disease mutations fail to stabilize ALK3 (PMID:24904118). Beyond hepcidin signaling, HFE inhibits iron efflux from macrophages independently of its TfR1 interaction (PMID:12429850, PMID:15044462), suppresses CD8+ T-lymphocyte activation through its α1–α2 domains (PMID:24643698), and negatively regulates RIG-I-like receptor antiviral signaling by binding MAVS and routing it to SQSTM1/p62-dependent autophagic degradation (PMID:10756356).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1998 High

    Established that HFE is genuinely required for iron homeostasis in vivo, anchoring the gene's physiological role before any molecular mechanism was known.

    Evidence Targeted Hfe knockout mouse with hepatic iron quantification and histochemistry

    PMID:9482913

    Open questions at the time
    • Does not identify the molecular partner or signaling output through which HFE regulates iron
    • Hepatocyte-versus-macrophage site of action not resolved
  2. 1999 High

    Defined the central molecular interaction by showing HFE competes with diferric transferrin for an overlapping site on TfR1, explaining how HFE could modulate iron uptake.

    Evidence SPR and radioligand inhibition assays with soluble recombinant HFE, TfR, and Fe-Tf; co-IP/Western in primary human duodenal enterocytes

    PMID:10556042 PMID:9990067

    Open questions at the time
    • In vitro stoichiometry does not establish the downstream signaling consequence of competition
    • Tissue association does not prove which cells sense iron systemically
  3. 1999 Medium

    Connected HFE–TfR1 binding to a cellular outcome, showing HFE overexpression lowers the labile iron pool and activates IRPs.

    Evidence Tetracycline-inducible HFE HeLa line with iron uptake, IRP activity, and ferritin/TfR Western readouts

    PMID:10572108

    Open questions at the time
    • HeLa is not a hepatocyte or enterocyte model
    • Does not link the labile iron change to hepcidin regulation
  4. 2000 High

    Provided the atomic-resolution architecture of the HFE–TfR complex, revealing the MHC-groove helices contact the TfR dimerization domain and that binding rearranges the TfR dimer interface.

    Evidence 2.8 Å X-ray crystal structure of the HFE–TfR ectodomain complex

    PMID:10638746

    Open questions at the time
    • Structure does not capture the membrane-bound signaling complex or HFE engagement with hepcidin machinery
    • Conformational link between TfR binding and HFE release is structural inference only
  5. 2002 Medium

    Separated HFE functions by showing it inhibits macrophage iron efflux independently of TfR1 competition, indicating more than one biochemical activity.

    Evidence Iron efflux assays in THP-1 and primary macrophages with the H41D mutant that retains TfR1 binding but loses efflux inhibition

    PMID:12429850

    Open questions at the time
    • Molecular target mediating efflux inhibition not identified
    • Single-lab cell assay without in vivo confirmation
  6. 2003 High

    Demonstrated that the H63D-equivalent allele is a partial loss-of-function, ordering the disease alleles into a severity series.

    Evidence H67D and C294Y knock-in mice with hepatic iron quantification across an allelic series

    PMID:14673107

    Open questions at the time
    • Does not define which molecular function each mutation disrupts
    • Diet- and age-dependent penetrance not characterized
  7. 2004 High

    Refined the binding mechanism by showing HFE–TfR1 and Fe-Tf–TfR1 competition occurs per chain without negative cooperativity, and that competition alters HFE trafficking.

    Evidence Engineered heterodimeric TfR binding studies plus transfected cell-line localization

    PMID:15044462 PMID:15056661

    Open questions at the time
    • The trafficking outcome's relevance to systemic hepcidin control not yet established
    • TfR1-independent efflux mechanism still molecularly undefined
  8. 2008 High

    Established the sensing logic of the system: HFE induces hepcidin specifically when NOT bound to TfR1, defining displacement by Fe-Tf as the trigger.

    Evidence Knock-in TfR1 mutants forcing or preventing HFE interaction, plus liver-specific HFE transgenic rescue in Hfe-null mice; hepcidin and iron readouts

    PMID:18316026

    Open questions at the time
    • Does not identify the receptor through which free HFE signals to hepcidin
    • Hepatocyte iron-uptake contribution versus signaling contribution unresolved
  9. 2008 Medium

    Localized HFE's iron-uptake control to the TfR1-mediated hepatocyte pathway specifically, sharpening the sensor model.

    Evidence Dual-concentration 125I-Tf/59Fe uptake assays in primary Hfe-/- versus wild-type hepatocytes

    PMID:18393371

    Open questions at the time
    • Does not connect altered hepatocyte uptake to hepcidin output
    • Tfr1-independent pathway identity (Tfr2) inferred, not proven
  10. 2010 Medium

    Clarified the relationship to TfR2, showing both proteins are required in hepatocytes for hepcidin regulation while no stable Hfe–Tfr2 complex is detected in vivo, and HFE is limiting.

    Evidence Hepatocyte-specific AAV Hfe delivery in Hfe-null and Tfr2-deficient mice; co-IP of endogenous liver lysates

    PMID:20177050

    Open questions at the time
    • Negative co-IP does not exclude a transient or low-affinity interaction
    • Mechanism by which Tfr2 contributes to the same pathway not defined
  11. 2012 Medium

    Showed Hfe can induce hepcidin even without Tfr2, indicating Tfr2 is not strictly required for HFE-dependent hepcidin induction.

    Evidence Transgenic Hfe overexpression in Tfr2-null mice; hepcidin mRNA and iron parameters; co-IP

    PMID:22460705

    Open questions at the time
    • Apparent tension with the earlier co-requirement finding not fully reconciled
    • Single-lab genetic system
  12. 2014 High

    Identified the receptor mechanism for HFE-driven hepcidin: HFE stabilizes the BMP type I receptor ALK3 by blocking its degradation, increasing surface ALK3 and Smad signaling.

    Evidence HFE overexpression in Hep3B with co-IP, ubiquitination assays, surface ALK3 flow cytometry, phospho-Smad blots, BMP inhibitor, and Hfe-/- mouse liver

    PMID:24904118

    Open questions at the time
    • Does not show how TfR1 displacement is coupled to ALK3 engagement
    • Structural basis of HFE–ALK3 interaction unknown
  13. 2014 Medium

    Defined an iron-independent immunoregulatory function, with HFE suppressing CD8+ T-cell activation via its α1–α2 domains.

    Evidence HFE transfection in APC model cells co-cultured with antigen-specific CD8+ T cells; domain-deletion and W81A mutants; MIP-1β and 4-1BB readouts

    PMID:24643698

    Open questions at the time
    • Molecular target of the α1–α2-mediated suppression not identified
    • In vivo immunological relevance not established
  14. 2015 High

    Placed HFE genetically within the HJV-dependent BMP–Smad pathway, establishing that HFE-driven hepcidin regulation requires HJV-mediated signaling.

    Evidence Hfe-/-Hjv-/- double-knockout epistasis with iron, hepcidin, and acute-iron-induced Smad1/5/8 phosphorylation readouts (two independent studies)

    PMID:25608116 PMID:25609138

    Open questions at the time
    • Whether HFE and HJV act on the same receptor complex molecularly not resolved here
    • Order of HFE relative to HJV in the pathway inferred from epistasis
  15. 2020 Medium

    Extended HFE into innate antiviral immunity, showing it binds MAVS and drives its SQSTM1/p62-dependent autophagic degradation to dampen type I interferon responses.

    Evidence Co-IP of HFE–MAVS and HFE–SQSTM1; Hfe knockdown/knockout cells and mice; IFN measurement, autophagy flux, and viral infection models

    PMID:32746697

    Open questions at the time
    • Direct versus indirect HFE–MAVS binding not structurally resolved
    • Relationship between this function and iron-sensing role unclear
  16. 2023 High

    Assigned the major non-redundant function of hepatocyte TfR1 in iron homeostasis to its interaction with HFE, cementing the displacement-based sensor model and its relevance to β-thalassemia.

    Evidence Hepatocyte-specific Tfrc knockout, Tfrc/Hfe double knockout, and β-thalassemia mouse models with hepcidin, iron, erythropoietin, and erythroferrone readouts

    PMID:36322932

    Open questions at the time
    • Does not resolve how the sensing complex transitions to ALK3/HJV signaling at the molecular level
    • Quantitative contribution of HFE displacement versus other inputs to physiological hepcidin setpoint not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How free HFE, released from TfR1 upon transferrin saturation, is physically coupled to ALK3 stabilization and HJV-dependent BMP–Smad signaling at the hepatocyte membrane remains the central unresolved mechanistic question.
  • No structure of the HFE–ALK3 or HFE–HJV signaling complex
  • Mechanism integrating the TfR1, ALK3/HJV, macrophage efflux, and antiviral functions into one protein not unified
  • Whether HFE engages distinct partners in different tissues (hepatocyte, macrophage, RPE) unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0060089 molecular transducer activity 3 GO:0140313 molecular sequestering activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005739 mitochondrion 1
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 2 R-HSA-168256 Immune System 2
Partners
ALK3B2MHJVMAVSSQSTM1TFR2TFRC
Complex memberships
HFE–TfR1 complexHFE–TfR1–transferrin sensing complex

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Crystal structure of HFE complexed with the extracellular portion of transferrin receptor (TfR) at 2.8 Å resolution shows two HFE molecules binding each side of a twofold-symmetric TfR dimer. HFE lies parallel to the membrane with its helices (counterpart of the MHC peptide-binding groove) making extensive contacts with TfR dimerization-domain helices. The HFE–TfR complex differs from the TfR-alone structure in domain arrangement and dimer interface, providing a mechanism for communicating binding events between TfR chains. X-ray crystallography (2.8 Å crystal structure of HFE–TfR extracellular complex) Nature High 10638746
1999 HFE competes with diferric transferrin (Fe-Tf) for binding to TfR by binding at or near the Fe-Tf binding site on TfR. Inhibition assays show the Fe-Tf:TfR:HFE ternary complex contains one Fe-Tf and one HFE bound to a TfR homodimer, with HFE reducing the apparent affinity of TfR for Fe-Tf. Radioactivity-based and biosensor (surface plasmon resonance) binding/inhibition assays with soluble recombinant proteins Journal of Molecular Biology High 10556042
2004 HFE and Fe-Tf compete directly for their overlapping binding sites on each TfR polypeptide chain without negative cooperativity between the two TfR chains. A heterodimeric TfR engineered so one chain binds only HFE and the other only Fe-Tf confirmed the absence of cooperativity. Cell-line experiments showed this competition alters HFE trafficking patterns, indicating physiological relevance. Heterodimeric mutant TfR binding studies (soluble proteins) combined with transfected cell-line localization experiments The Journal of Biological Chemistry High 15056661
1999 HFE protein is physically associated with TfR and β2-microglobulin in crypt enterocytes of human duodenum (as in placenta). Crypt enterocytes showed dramatically higher transferrin-bound iron uptake than villus cells, consistent with HFE modulating transferrin-bound iron uptake to sense body iron stores. Immunocytochemistry, co-immunoprecipitation/Western blot of crypt enterocyte fractions, iron uptake assays with isolated crypt vs. villus cells Proceedings of the National Academy of Sciences of the United States of America High 9990067
1999 Stable overexpression of HFE in HeLa cells decreases iron uptake from diferric transferrin and activates iron-regulatory proteins (IRPs), implying HFE reduces the intracellular labile iron pool. This IRP activation is accompanied by downregulation of ferritin and upregulation of transferrin receptor. Stably transfected HeLa cell line (tetracycline-inducible HFE), iron uptake assays, IRP activity assays, Western blot for ferritin and TfR Blood Medium 10572108
1998 Targeted disruption of the murine Hfe gene produces systemic iron overload (8-fold elevated hepatic iron at 10 weeks, elevated transferrin saturation) with iron predominantly in periportal hepatocytes, establishing that HFE is required for regulation of iron homeostasis in vivo. Gene knockout mouse model; hepatic iron quantification, transferrin saturation measurement, histochemical iron staining Proceedings of the National Academy of Sciences of the United States of America High 9482913
2008 Hfe regulates hepcidin expression as a component of the TfR1 sensing complex. Mutations forcing constitutive Hfe–TfR1 interaction caused iron overload with inappropriately low hepcidin; mutations preventing the interaction caused iron deficiency with inappropriately high hepcidin. Liver-specific Hfe overexpression in Hfe-null mice increased hepcidin and caused iron deficiency. Together these data indicate Hfe induces hepcidin expression when NOT bound to TfR1. Knock-in mouse strains with TfR1 mutations promoting or preventing Hfe interaction; liver-specific transgenic Hfe overexpression in Hfe-/- background; hepcidin mRNA quantification, iron parameter measurement Cell Metabolism High 18316026
2002 Wild-type HFE raises cellular iron by inhibiting iron efflux from monocyte/macrophage cells (THP-1 and primary macrophages), independently of its competition with transferrin for TfR1. The HH-associated mutant H41D retains TfR1 binding but loses the ability to inhibit iron release, indicating these are separable functions of HFE. Iron efflux assays in THP-1 monocyte cell line and primary macrophages from healthy individuals and HH patients; H41D mutant functional comparison; transferrin competition assay Proceedings of the National Academy of Sciences of the United States of America Medium 12429850
2014 HFE interacts with the BMP type I receptor ALK3, inhibiting ALK3 ubiquitination and proteasomal degradation, thereby increasing ALK3 protein levels and its accumulation at the cell surface. This stabilization of ALK3 by HFE increases Smad1/5/8 phosphorylation and hepcidin expression; BMP pathway inhibition abolishes HFE-induced hepcidin upregulation. Both C282Y and H63D HFE mutants fail to increase ALK3 cell-surface expression. Hfe deletion in mice reduces hepatic ALK3 protein. HFE overexpression in Hep3B cells; co-immunoprecipitation (HFE–ALK3 interaction); ubiquitination assays; flow cytometry (cell-surface ALK3); phospho-Smad Western blot; BMP inhibitor treatment; Hfe-/- mouse liver Western blot Blood High 24904118
2010 Hepatocyte-specific AAV-mediated expression of Hfe in Hfe-null mice increases hepcidin mRNA and lowers hepatic iron and transferrin saturation, while Hfe expression in Tfr2-deficient mice has no effect on iron levels (and vice versa). Co-IP of liver lysates did not detect physical interaction between Hfe and Tfr2 in vivo, suggesting Hfe is limiting in the Hfe/Tfr2 complex that regulates hepcidin, and that both proteins are required in hepatocytes for hepcidin regulation. Hepatocyte-specific AAV2/8 gene delivery; hepcidin mRNA quantification; liver and serum iron measurement; co-immunoprecipitation of endogenous liver lysates Blood Medium 20177050
2012 Hepatocellular overexpression of Hfe induces hepcidin and causes iron deficiency even in Tfr2-null mice, demonstrating that Tfr2 is not required for Hfe-dependent hepcidin induction. Co-IP of liver lysates did not detect Hfe–Tfr2 physical interaction in vivo. Transgenic Hfe overexpression in Tfr2(Y245X/Y245X) mice; hepcidin mRNA measurement; blood iron parameters; co-immunoprecipitation of liver lysates American Journal of Hematology Medium 22460705
2015 Genetic epistasis in mice demonstrates Hfe and Hjv operate in the same pathway for hepcidin regulation: Hfe(-/-)Hjv(-/-) double-knockout mice are indistinguishable from single Hjv(-/-) mice in hepcidin suppression, iron overload, and Smad signaling, indicating Hfe functions upstream of or requires HJV-dependent BMP-Smad signaling. Double-knockout mouse generation (Hfe-/-Hjv-/-); serum and hepatic iron quantification; hepcidin mRNA; Smad1/5/8 phosphorylation Western blot; dietary iron challenge Journal of Molecular Medicine High 25609138
2015 In Hfe(-/-)Hjv(-/-) double-knockout mice, iron-induced phosphorylation of Smad1/5/8 is absent (as in Hjv(-/-) alone), and hepcidin cannot be induced by acute iron delivery, confirming that HFE-dependent hepcidin regulation requires HJV-mediated BMP-Smad signaling. Double-knockout mice; acute iron gavage; Smad1/5/8 phosphorylation Western blot; hepcidin mRNA quantification Antioxidants & Redox Signaling High 25608116
2006 Hfe is required for establishment of basal hepcidin levels but is dispensable for hepcidin upregulation in response to iron loading or acute inflammation (LPS). In contrast, LPS-induced hepcidin regulation is TLR-4 dependent. Hepatic ferroportin regulation by iron and LPS is largely independent of Hfe. Hfe-/- and β2m-/- mice subjected to iron deprivation, iron loading, and LPS challenge; hepcidin mRNA quantification; ferroportin protein measurement; TLR-4 knockout comparison American Journal of Physiology - Gastrointestinal and Liver Physiology Medium 16565419
2004 In HT29 colonic cells (a duodenal model), stable HFE expression increases ferritin by inhibiting iron efflux rather than by affecting TfR1-mediated uptake. This effect is independent of HFE's interaction with TfR1 (shown using the W81A mutant with greatly reduced TfR1 affinity) and is associated with decreased hephaestin mRNA. Stably transfected HT29 cells; ferritin Western blot; iron uptake and efflux assays; W81A TfR1-binding mutant comparison; hephaestin mRNA RT-PCR The Journal of Biological Chemistry Medium 15044462
2008 In Hfe-knockout hepatocytes, Tfr1-mediated (low-concentration) transferrin-bound iron uptake is increased 40–70% compared to iron-loaded wild-type hepatocytes with similar Tfr1 expression, showing Hfe specifically regulates the Tfr1-mediated hepatocyte iron uptake pathway. The high-capacity Tfr1-independent (putative Tfr2) pathway is not affected by absence of Hfe. Primary hepatocytes from Hfe-/- and wild-type mice; dual-concentration 125I-Tf/59Fe uptake assays distinguishing Tfr1 and Tfr1-independent pathways; Tfr1 and Tfr2 mRNA/protein quantification Hepatology Medium 18393371
2003 Knock-in mice carrying H67D (murine equivalent of human H63D) show hepatic iron loading that is intermediate between wild-type and C294Y homozygotes. H67D/H67D, C294Y/C294Y, and H67D/C294Y compound heterozygotes all develop hepatic iron loading, establishing that the H67D allele causes partial loss of Hfe function. Knock-in mouse generation; hepatic iron quantification at 10 weeks on standard diet Proceedings of the National Academy of Sciences of the United States of America High 14673107
2005 HFE cross-talks with the MHC class I antigen presentation pathway: PBMCs from HH patients with the C282Y mutation show enhanced endocytosis and premature dissociation of MHC class I–β2m–peptide complexes, producing low-stability heterotrimers and increased free class I heavy chains at the cell surface. Earlier peptide loading and ER maturation of MHC class I are also observed in C282Y cells. FACS analysis of MHC class I surface expression and endocytosis rate; biochemical thermostability assays of MHC class I complexes; comparison of patient (C282Y) PBMCs vs. normal PBMCs Blood Medium 15840699
2014 Wild-type HFE (but not C282Y-mutated HFE) inhibits CD8+ T-lymphocyte activation (MIP-1β secretion and 4-1BB expression) when expressed in antigen-presenting cells. This inhibition is independent of MHC class I surface levels, β2-microglobulin competition, or HFE–TfR interaction. The α1-α2 domains of HFE are responsible for this immunosuppressive activity. Transient HFE transfection in APC model cells; co-culture with antigen-specific CD8+ T lymphocytes; cytokine ELISA (MIP-1β); 4-1BB flow cytometry; domain deletion mutants; W81A (TfR1-binding) mutant control European Journal of Immunology Medium 24643698
2020 HFE acts as a negative regulator of RIG-I-like receptor (RLR)-mediated type I interferon signaling by binding to MAVS (mitochondrial antiviral signaling protein) and mediating its autophagic degradation via SQSTM1/p62. RNA virus infection inhibits the HFE–MAVS interaction, blocking MAVS autophagic degradation. Hfe depletion abrogates MAVS degradation and enhances antiviral immune responses. Co-immunoprecipitation (HFE–MAVS and HFE–SQSTM1 interactions); Hfe knockdown/knockout cells and mice; type I IFN and cytokine measurement; autophagy flux assays; viral infection models Autophagy Medium 32746697
2000 HFE protein is expressed on the cell surface of gastric epithelial cells, tissue macrophages, and circulating monocytes/granulocytes. The C282Y mutation reduces but does not completely prevent cell-surface presentation of HFE in these primary human cell types. Immunocytochemistry of tissue sections; immunostaining of isolated leukocyte populations from normal subjects and HH patients; antisera against two distinct HFE peptides Haematologica Medium 10756356
2006 HFE mRNA is expressed almost exclusively in the retinal pigment epithelium (RPE) within the retina, and HFE protein localizes specifically to the basolateral membrane of RPE cells. HFE-interacting proteins TfR1, TfR2, and β2-microglobulin are co-expressed in the retina, consistent with HFE regulating iron homeostasis at the RPE basolateral membrane. RT-PCR; in situ hybridization; immunofluorescence; immunogold electron microscopy in mouse retina Investigative Ophthalmology & Visual Science Medium 17003411
2023 Hepatocyte-specific TfR1 knockout mice show inappropriately high hepcidin relative to serum/liver iron, and combined hepatocyte Tfrc/Hfe double knockout abolishes the iron phenotype seen in Tfrc-only knockout mice, establishing that the major non-redundant function of hepatocyte TfR1 in iron homeostasis is to interact with HFE to regulate hepcidin. This pathway is modulated by serum iron and contributes to hepcidin suppression and iron overload in murine β-thalassemia. Hepatocyte-specific Tfrc conditional knockout mice (Tfrcfl/fl;Alb-Cre); double knockout with Hfe and β-thalassemia models; hepcidin mRNA, serum/liver iron, erythropoietin, erythroferrone measurements; iron challenge experiments Blood High 36322932
2009 Expression of H63D and C282Y HFE variants in neuroblastoma SH-SY5Y cells alters the labile iron pool and selectively increases secretion of MCP-1 (monocyte chemoattractant protein-1) compared to wild-type HFE. MCP-1 secretion is tightly correlated with intracellular iron status, but the HFE genotype also influences MCP-1 independently of iron level, and modifies the pharmacological effect of minocycline on MCP-1. Stably transfected neuroblastoma cells expressing HFE variants; multiplex cytokine immunoassay; iron manipulation (ferric ammonium citrate, DFO); labile iron pool measurement Journal of Neuroinflammation Low 19228389
2003 HFE gene is expressed in rat hepatocytes (parenchymal cells) in addition to non-parenchymal liver cells, with highest expression in liver among all tissues. This raises the possibility that HFE has a direct role in hepatocyte iron metabolism, not only in Kupffer cells. Northern blot (tissue expression); real-time PCR of fractionated liver cell populations (parenchymal vs. non-parenchymal); gene cloning and exon-intron structure determination Journal of Hepatology Low 12927914

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 HFE gene knockout produces mouse model of hereditary hemochromatosis. Proceedings of the National Academy of Sciences of the United States of America 442 9482913
2010 EASL clinical practice guidelines for HFE hemochromatosis. Journal of hepatology 351 20471131
2001 HFE gene and hereditary hemochromatosis: a HuGE review. Human Genome Epidemiology. American journal of epidemiology 332 11479183
2000 Crystal structure of the hereditary haemochromatosis protein HFE complexed with transferrin receptor. Nature 285 10638746
2008 The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression. Cell metabolism 279 18316026
1998 Porphyria cutanea tarda, hepatitis C, and HFE gene mutations in North America. Hepatology (Baltimore, Md.) 196 9620340
1999 Association of HFE protein with transferrin receptor in crypt enterocytes of human duodenum. Proceedings of the National Academy of Sciences of the United States of America 195 9990067
2001 Prevalence of C282Y and H63D mutations in the hemochromatosis (HFE) gene in the United States. JAMA 184 11325323
2005 Bone mineral density in men with genetic hemochromatosis and HFE gene mutation. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 162 15928800
1999 The hemochromatosis protein HFE competes with transferrin for binding to the transferrin receptor. Journal of molecular biology 154 10556042
2004 HFE and transferrin directly compete for transferrin receptor in solution and at the cell surface. The Journal of biological chemistry 115 15056661
2015 HFE gene: Structure, function, mutations, and associated iron abnormalities. Gene 112 26456104
2002 The hemochromatosis protein HFE inhibits iron export from macrophages. Proceedings of the National Academy of Sciences of the United States of America 106 12429850
2003 Association between hemochromatosis (HFE) gene mutation carrier status and the risk of colon cancer. Journal of the National Cancer Institute 103 12529348
2004 The origin and spread of the HFE-C282Y haemochromatosis mutation. Human genetics 101 15290237
1998 Hemochromatosis in Ireland and HFE. Blood cells, molecules & diseases 94 9851896
2011 HFE gene variants affect iron in the brain. The Journal of nutrition 91 21346098
2014 HFE interacts with the BMP type I receptor ALK3 to regulate hepcidin expression. Blood 86 24904118
2009 HFE-associated hereditary hemochromatosis. Genetics in medicine : official journal of the American College of Medical Genetics 80 19444013
1999 HFE downregulates iron uptake from transferrin and induces iron-regulatory protein activity in stably transfected cells. Blood 78 10572108
2011 Non-HFE hepatic iron overload. Seminars in liver disease 73 21901660
2010 Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice. Blood 71 20177050
2003 Mutations in the hemochromatosis gene (HFE), Parkinson's disease and parkinsonism. Neuroscience letters 71 12902032
2002 H63D mutation in the HFE gene increases iron overload in beta-thalassemia carriers. Haematologica 69 11869934
2007 Non-HFE haemochromatosis. World journal of gastroenterology 68 17729390
2003 Contribution of the H63D mutation in HFE to murine hereditary hemochromatosis. Proceedings of the National Academy of Sciences of the United States of America 68 14673107
2000 Contribution of different HFE genotypes to iron overload disease: a pooled analysis. Genetics in medicine : official journal of the American College of Medical Genetics 66 11399207
2001 Frequency and biochemical expression of C282Y/H63D hemochromatosis (HFE) gene mutations in the healthy adult population in Italy. Journal of hepatology 64 11394651
2006 HFE mutations and Alzheimer's disease. Journal of Alzheimer's disease : JAD 63 17119292
1999 Spectrum of mutations in the HFE gene implicated in haemochromatosis and porphyria. Human molecular genetics 61 10401000
2005 Non-HFE hemochromatosis. Seminars in liver disease 57 16315138
2001 Molecular aspects of iron absorption and HFE expression. Gastroenterology 56 11729128
2017 Pathophysiological consequences and benefits of HFE mutations: 20 years of research. Haematologica 54 28280078
2006 Distinct requirements for Hfe in basal and induced hepcidin levels in iron overload and inflammation. American journal of physiology. Gastrointestinal and liver physiology 54 16565419
2000 Cell surface expression of HFE protein in epithelial cells, macrophages, and monocytes. Haematologica 52 10756356
2001 HFE gene mutations analysis in Basque hereditary haemochromatosis patients and controls. European journal of human genetics : EJHG 50 11840200
2005 HFE cross-talks with the MHC class I antigen presentation pathway. Blood 46 15840699
2020 HFE inhibits type I IFNs signaling by targeting the SQSTM1-mediated MAVS autophagic degradation. Autophagy 45 32746697
2006 Hemochromatosis (HFE) gene mutations and peripheral neuropathy during antiretroviral therapy. AIDS (London, England) 44 16847405
2006 Expression and polarized localization of the hemochromatosis gene product HFE in retinal pigment epithelium. Investigative ophthalmology & visual science 43 17003411
2001 Hereditary hemochromatosis since discovery of the HFE gene. Clinical chemistry 43 11427444
2014 HFE-related hemochromatosis: an update for the rheumatologist. Current rheumatology reports 42 24264720
2012 Transgenic HFE-dependent induction of hepcidin in mice does not require transferrin receptor-2. American journal of hematology 42 22460705
2020 The roles of iron and HFE genotype in neurological diseases. Molecular aspects of medicine 41 32654761
2004 Expression of the hereditary hemochromatosis protein HFE increases ferritin levels by inhibiting iron export in HT29 cells. The Journal of biological chemistry 41 15044462
1999 The hereditary hemochromatosis gene (HFE): a MHC class I-like gene that functions in the regulation of iron homeostasis. Immunologic research 41 10580641
2019 Hemochromatosis: Hereditary hemochromatosis and HFE gene. Vitamins and hormones 38 30798813
2006 Iron Imports. VI. HFE and regulation of intestinal iron absorption. American journal of physiology. Gastrointestinal and liver physiology 38 16537971
2011 Iron metabolism and the role of HFE gene polymorphisms in Wilson disease. Liver international : official journal of the International Association for the Study of the Liver 36 22098612
2003 Hemochromatosis (HFE) gene mutations and response to chloroquine in porphyria cutanea tarda. Archives of dermatology 35 12622622
2010 Factors influencing disease phenotype and penetrance in HFE haemochromatosis. Human genetics 34 20607553
2008 Function of the hemochromatosis protein HFE: Lessons from animal models. World journal of gastroenterology 34 19058322
2023 Regulation of iron homeostasis by hepatocyte TfR1 requires HFE and contributes to hepcidin suppression in β-thalassemia. Blood 33 36322932
2014 Molecular basis of HFE-hemochromatosis. Frontiers in pharmacology 33 24653703
2012 Non-HFE hemochromatosis. Revista brasileira de hematologia e hemoterapia 32 23049448
2019 Diagnosis and Treatment of Genetic HFE-Hemochromatosis: The Danish Aspect. Gastroenterology research 29 31636772
2005 Iron stores modulate hepatic hepcidin expression by an HFE-independent pathway. Digestion 29 16103673
2015 Hfe and Hjv exhibit overlapping functions for iron signaling to hepcidin. Journal of molecular medicine (Berlin, Germany) 28 25609138
2011 HFE, MTHFR, and FGFR4 genes polymorphisms and breast cancer in Brazilian women. Molecular and cellular biochemistry 28 21625954
2009 Influence of HFE variants and cellular iron on monocyte chemoattractant protein-1. Journal of neuroinflammation 28 19228389
2005 HFE gene mutations in susceptibility to childhood leukemia: HuGE review. Genetics in medicine : official journal of the American College of Medical Genetics 28 15775751
2002 A previously undescribed nonsense mutation of the HFE gene. Clinical genetics 28 11903354
2000 Differential HFE allele expression in hemochromatosis heterozygotes. Gastroenterology 28 11040194
1999 Mutation analysis of the HFE gene in Brazilian populations. Blood cells, molecules & diseases 28 10660479
2013 Non-HFE hemochromatosis: pathophysiological and diagnostic aspects. Clinics and research in hepatology and gastroenterology 26 24321703
2011 Natural history and management of HFE-hemochromatosis. Seminars in liver disease 26 21901659
2010 Hepcidin and Hfe in iron overload in beta-thalassemia. Annals of the New York Academy of Sciences 26 20712796
2002 Frequency of the HFE gene mutations in five Italian populations. Blood cells, molecules & diseases 26 12547216
2001 Iron status and HFE genotype in erythrocyte pyruvate kinase deficiency: study of Italian cases. Blood cells, molecules & diseases 26 11482880
2017 The role of TMPRSS6 and HFE variants in iron deficiency anemia in celiac disease. American journal of hematology 25 29194702
2000 HFE gene mutations in coronary atherothrombotic disease. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 25 10719381
2009 HFE polymorphisms affect cellular glutamate regulation. Neurobiology of aging 24 19560233
2003 Association between the HFE mutations and longevity: a study in Sardinian population. Mechanisms of ageing and development 24 12714263
2002 Mutations in the hemochromatosis gene (HFE) and stroke. Stroke 24 12364722
2008 Clinical penetrance of C282Y homozygous HFE hemochromatosis. Expert review of hematology 23 21082925
2003 Structure and liver cell expression pattern of the HFE gene in the rat. Journal of hepatology 23 12927914
2018 HFE Genotype Restricts the Response to Paraquat in a Mouse Model of Neurotoxicity. Journal of neurochemistry 22 29315562
2013 Hfe mutations and iron overload in patients with alcoholic liver disease. Arquivos de gastroenterologia 22 23657305
2007 The H63D variant in the HFE gene predisposes to arthralgia, chondrocalcinosis and osteoarthritis. Annals of the rheumatic diseases 22 17284543
2007 HFE gene in primary and secondary hepatic iron overload. World journal of gastroenterology 22 17729389
1999 Mutations of the HFE gene and the risk of hepatocellular carcinoma. Blood cells, molecules & diseases 22 10660482
2008 The role of Hfe in transferrin-bound iron uptake by hepatocytes. Hepatology (Baltimore, Md.) 20 18393371
2017 A role for sex and a common HFE gene variant in brain iron uptake. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 19 28350201
2015 HJV and HFE Play Distinct Roles in Regulating Hepcidin. Antioxidants & redox signaling 19 25608116
2014 The WT hemochromatosis protein HFE inhibits CD8⁺ T-lymphocyte activation. European journal of immunology 19 24643698
2012 Hemochromatosis gene (HFE) polymorphisms and risk of type 2 diabetes mellitus: a meta-analysis. American journal of epidemiology 19 22908207
2002 HFE gene mutations and iron metabolism in Wilson's disease. Liver 19 12445172
2009 Hereditary hemochromatosis gene (HFE) variants are associated with birth weight and childhood leukemia risk. Pediatric blood & cancer 18 19711434
2002 Hemochromatosis (HFE) and transferrin receptor-1 (TFRC1) genes in sporadic porphyria cutanea tarda (sPCT). Cellular and molecular biology (Noisy-le-Grand, France) 18 11929045
2000 Prevalence and clinical significance of HFE gene mutations in patients with iron overload. The American journal of gastroenterology 18 11051367
2002 HFE and non-HFE hemochromatosis. International journal of hematology 17 12416729
1999 Update on hereditary hemochromatosis and the HFE gene. Mayo Clinic proceedings 17 10488796
2021 Dietary Iron Overload and Hfe Related Hemochromatosis Alter Hepatic Mitochondrial Function. Antioxidants (Basel, Switzerland) 16 34829689
2014 Diagnostic evaluation of hereditary hemochromatosis (HFE and non-HFE). Hematology/oncology clinics of North America 16 25064704
2009 HFE gene mutations and iron status of Brazilian blood donors. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 16 20027482
2008 Does the SLC40A1 gene modify HFE-related haemochromatosis phenotypes? Annals of hematology 16 18820912
2005 Hereditary hemochromatosis gene (HFE) mutations C282Y, H63D and S65C in patients with idiopathic dilated cardiomyopathy. European journal of heart failure 16 15642540
2004 Iron, the HFE gene, and hepatitis C. Clinics in liver disease 16 15464655
2001 C282Y and H63D mutations of HFE gene in patients with advanced alcoholic liver disease. Revista espanola de enfermedades digestivas 16 11469076
2000 The structure and function of HFE. BioEssays : news and reviews in molecular, cellular and developmental biology 16 10878571

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