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1.  Absorption of Manganese and Iron in a Mouse Model of Hemochromatosis 
PLoS ONE  2013;8(5):e64944.
Hereditary hemochromatosis, an iron overload disease associated with excessive intestinal iron absorption, is commonly caused by loss of HFE gene function. Both iron and manganese absorption are regulated by iron status, but the relationships between the transport pathways of these metals and how they are affected by HFE-associated hemochromatosis remain poorly understood. Loss of HFE function is known to alter the intestinal expression of DMT1 (divalent metal transporter-1) and Fpn (ferroportin), transporters that have been implicated in absorption of both iron and manganese. Although the influence of HFE deficiency on dietary iron absorption has been characterized, potential effects on manganese metabolism have yet to be explored. To investigate the role of HFE in manganese absorption, we characterized the uptake and distribution of the metal in Hfe−/− knockout mice after intravenous, intragastric, and intranasal administration of 54Mn. These values were compared to intravenous and intragastric administration of 59Fe. Intestinal absorption of 59Fe was increased and clearance of injected 59Fe was also increased in Hfe−/− mice compared to controls. Hfe−/− mice displayed greater intestinal absorption of 54Mn compared to wild-type Hfe+/+ control mice. After intravenous injection, the distribution of 59Fe to heart and liver was greater in Hfe−/− mice but no remarkable differences were observed for 54Mn. Although olfactory absorption of 54Mn into blood was unchanged in Hfe−/− mice, higher levels of intranasally-instilled 54Mn were associated with Hfe−/− brain compared to controls. These results show that manganese transport and metabolism can be modified by HFE deficiency.
doi:10.1371/journal.pone.0064944
PMCID: PMC3660331  PMID: 23705020
2.  Clinical, Pathological, and Molecular Correlates in Ferroportin Disease. A Study Of Two Novel Mutations 
Journal of hepatology  2008;49(4):664-671.
Background/Aims
Clinico-pathological manifestations of Ferroportin (Fpn) Disease (FD) are heterogeneous, with some patients presenting with iron overload predominantly in macrophages (“M” phenotype), others predominantly in hepatocytes (“H” phenotype). This appears to reflect functional heterogeneity of Fpn mutants, with loss-of-function generally resulting in the M type.
Methods
Two unrelated probands with “non-HFE” hemochromatosis were screened for Fpn mutations. Mutants were functionally characterized by immunofluorescence microscopy, evaluation of their ability to bind hepcidin and export iron, and by expressing them in zebrafish.
Results
Two novel Fpn mutations were identified: I152F in patient-1, presenting with typical M phenotype; and L233P in patient-2, presenting with ambiguous features (massive overload in both macrophages and hepatocytes). Molecular studies suggested loss of function in both cases. The I152F, normally localized on cell membrane and internalized by hepcidin, showed a unique “primary” deficit of iron export capability. The L233P did not appropriately traffic to cell surface. Loss of function was confirmed by expressing both mutants in vivo in zebrafish, resulting in iron limited erythropoiesis. Clinical manifestations were likely enhanced in both patients by nongenetic factors (HCV, alcohol).
Conclusions
The combination of careful review of clinico-pathological data with molecular studies can yield compelling explanations for phenotype heterogeneity in FD.
doi:10.1016/j.jhep.2008.05.028
PMCID: PMC2605969  PMID: 18713659
iron overload; ferroportin; hemochromatosis; hepcidin; zebrafish
3.  Molecular Diagnostic and Pathogenesis of Hereditary Hemochromatosis 
Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by enhanced intestinal absorption of dietary iron. Without therapeutic intervention, iron overload leads to multiple organ damage such as liver cirrhosis, cardiomyopathy, diabetes, arthritis, hypogonadism and skin pigmentation. Most HH patients carry HFE mutant genotypes: homozygosity for p.Cys282Tyr or p.Cys282Tyr/p.His63Asp compound heterozygosity. In addition to HFE gene, mutations in the genes that encode hemojuvelin (HJV), hepcidin (HAMP), transferrin receptor 2 (TFR2) and ferroportin (SLC40A1) have been associated with regulation of iron homeostasis and development of HH. The aim of this review was to identify the main gene mutations involved in the pathogenesis of type 1, 2, 3 and 4 HH and their genetic testing indication. HFE testing for the two main mutations (p.Cys282Tyr and p.His63Asp) should be performed in all patients with primary iron overload and unexplained increased transferrin saturation and/or serum ferritin values. The evaluation of the HJV p.Gly320Val mutation must be the molecular test of choice in suspected patients with juvenile hemochromatosis with less than 30 years and cardiac or endocrine manifestations. In conclusion, HH is an example that genetic testing can, in addition to performing the differential diagnostic with secondary iron overload, lead to more adequate and faster treatment.
doi:10.3390/ijms13021497
PMCID: PMC3291973  PMID: 22408404
hemochromatosis; primary iron overload; HFE; high-resolution melting; HJV; molecular diagnostic
4.  Function of the hemochromatosis protein HFE: Lessons from animal models 
Hereditary hemochromatosis (HH) is caused by chronic hyperabsorption of dietary iron. Progressive accumulation of excess iron within tissue parenchymal cells may lead to severe organ damage. The most prevalent type of HH is linked to mutations in the HFE gene, encoding an atypical major histocompatibility complex classImolecule. Shortly after its discovery in 1996, the hemochromatosis protein HFE was shown to physically interact with transferrin receptor 1 (TfR1) and impair the uptake of transferrin-bound iron in cells. However, these findings provided no clue why HFE mutations associate with systemic iron overload. It was later established that all forms of HH result from misregulation of hepcidin expression. This liver-derived circulating peptide hormone controls iron efflux from duodenal enterocytes and reticuloendothelial macrophages by promoting the degradation of the iron exporter ferroportin. Recent studies with animal models of HH uncover a crucial role of HFE as a hepatocyte iron sensor and upstream regulator of hepcidin. Thus, hepatocyte HFE is indispensable for signaling to hepcidin, presumably as a constituent of a larger iron-sensing complex. A working model postulates that the signaling activity of HFE is silenced when the protein is bound to TfR1. An increase in the iron saturation of plasma transferrin leads to displacement of TfR1 from HFE and assembly of the putative iron-sensing complex. In this way, iron uptake by the hepatocyte is translated into upregulation of hepcidin, reinforcing the concept that the liver is the major regulatory site for systemic iron homeostasis, and not merely an iron storage depot.
doi:10.3748/wjg.14.6893
PMCID: PMC2773850  PMID: 19058322
Hepcidin; Iron metabolism; Transferrin; Hemojuvelin; Bone morphogenetic proteins
5.  Autosomal-dominant hemochrom-atosis is associated with a mutation in the ferroportin (SLC11A3) gene 
Journal of Clinical Investigation  2001;108(4):619-623.
Hemochromatosis is a progressive iron overload disorder that is prevalent among individuals of European descent. It is usually inherited in an autosomal-recessive pattern and associated with missense mutations in HFE, an atypical major histocompatibility class I gene. Recently, we described a large family with autosomal-dominant hemochromatosis not linked to HFE and distinguished by early iron accumulation in reticuloendothelial cells. Through analysis of a large pedigree, we have determined that this disease maps to 2q32. The gene encoding ferroportin (SLC11A3), a transmembrane iron export protein, lies within a candidate interval defined by highly significant lod scores. We show that the iron-loading phenotype in autosomal-dominant hemochromatosis is associated with a nonconservative missense mutation in the ferroportin gene. This missense mutation, converting alanine to aspartic acid at residue 77 (A77D), was not seen in samples from 100 unaffected control individuals. We propose that partial loss of ferroportin function leads to an imbalance in iron distribution and a consequent increase in tissue iron accumulation.
PMCID: PMC209405  PMID: 11518736
6.  Hypoxia-Inducible Factor-2α Mediates the Adaptive Increase of Intestinal Ferroportin During Iron Deficiency in Mice 
Gastroenterology  2011;140(7):2044-2055.
Background & Aims
Iron deficiency and iron overload affect over a billion people, worldwide. Dietary iron absorption in the small intestine is required for systemic iron homeostasis. Ferroportin (FPN) is the only characterized, mammalian, basolateral iron exporter. Despite the importance of FPN in maintaining iron homeostasis, its in vivo mechanisms of regulation are unclear.
Methods
Systemic iron homeostasis was assessed in mice with intestine-specific disruption of genes encoding the von Hippel-Lindau tumor suppressor protein (Vhl), hypoxia-inducible factor (HIF)-1α, HIF-2α, and aryl hydrocarbon nuclear translocator (ARNT).
Results
We observed biphasic regulation of Fpn during iron deficiency. Fpn was rapidly induced under conditions of low iron, which required the transcription factor HIF-2α. Targeted disruption of HIF-2α in the intestine inhibited Fpn induction in mice with low iron, through loss of transcriptional activation. Analysis of the Fpn promoter and in vivo chromatin immunoprecipitation assays demonstrated that HIF-2α directly binds to the Fpn promoter and induces its expression, indicating a mechanism of transcriptional regulation of Fpn following changes in systemic levels of iron. During chronic iron deficiency, FPN protein levels also increased, via increased stability through a HIF-2α-independent pathway.
Conclusion
In mice, expression of the gene that encodes Fpn and its protein levels are regulated by distinct pathways to provide a rapid and sustained response to acute and chronic iron deficiency. Therapies that target FPN might be developed for patients with iron-related disorders..
doi:10.1053/j.gastro.2011.03.007
PMCID: PMC3109109  PMID: 21419768
ChIP assay; Hepcidin; diet; metabolism
7.  Brain and retinal ferroportin 1 dysregulation in polycythaemia mice 
Brain research  2009;1289:85-95.
Disruption of iron homeostatsis within the central nervous system (CNS) can lead to profound abnormalities during both development and aging in mammals. The radiation-induced polycythaemia (Pcm) mutation, a 58-bp microdeletion in the promoter region of ferroportin 1 (Fpn1), disrupts transcriptional and post-transcriptional regulation of this pivotal iron transporter. This regulatory mutation induces dynamic alterations in peripheral iron homeostatis such that newborn homozygous Pcm mice exhibit iron deficiency anemia with increased duodenal Fpn1 expression while adult homozygotes display decreased Fpn1 expression and anemia despite organismal iron overload. Herein we report the impact of the Pcm microdeletion on iron homeostasis in two compartments of the the central nervous system: brain and retina. At birth, Pcm homozygotes show a marked decrease in brain iron content and reduced levels of Fpn1 expression. Upregulation of transferrin receptor 1 (TfR1) in brain microvasculature appears to mediate the compensatory iron uptake during postnatal development and iron content in Pcm brain is restored to wildtype levels by 7 weeks of age. Similarly, changes in expression are transient and expression of Fpn1 and TfR1 is indistinguishable between Pcm homozygotes and wildtype by 12 weeks of age. Strikingly, the adult Pcm brain is effectively protected from the peripheral iron overload and maintains normal iron content. In contrast to Fpn1 downregulation in perinatal brain, the retina of Pcm homozygotes reveals increased levels of Fpn1 expression. While retinal morphology appears normal at birth and during early postnatal development, adult Pcm mice demonstrate a marked, age-dependent loss of photoreceptors. This phenotype demonstrates the importance of iron homeostasis in retinal health.
doi:10.1016/j.brainres.2009.06.098
PMCID: PMC2736625  PMID: 19596281
Polycythaemia; Ferroportin; Brain; Retina; Iron
8.  Effects of C282Y, H63D, and S65C HFE gene mutations, diet, and life-style factors on iron status in a general Mediterranean population from Tarragona, Spain 
Annals of Hematology  2010;89(8):767-773.
Mutations in the HFE gene result in iron overload and can produce hereditary hemochromatosis (HH), a disorder of iron metabolism characterized by increased intestinal iron absorption. Dietary quality, alcoholism and other life-style factors can increase the risk of iron overload, especially among genetically at risk populations. Polymorphisms of the HFE gene (C282Y, H63D and S65C) were measured together with serum ferritin (SF), transferrin saturation (TS) and hemoglobin, to measure iron status, in randomly-selected healthy subjects living in the Spanish Mediterranean coast (n = 815; 425 females, 390 males), 18 to 75 years of age. The intake of dietary components that affect iron absorption was calculated from 3-day dietary records. The presence of C282Y/H63D compound heterozygote that had a prevalence of 2.8% in males and 1.2% in females was associated with an elevated TS and SF. No subject was homozygous for C282Y or S65C. The C282Y heterozygote, H63D heterozygote and homozygote and H63D/S65C compound heterozygote genotypes were associated with increased TS relative to the wild type in the general population. These genotypes together with the alcohol and iron intake increase the indicators of iron status, while calcium intake decreases them. We did not observe any affect of the S65C heterozygote genotype on these levels. All the HFE genotypes except for the S65C heterozygote together with the alcohol, iron and calcium intake affect the indicators of iron status. The C282Y/H63D compound heterozygote genotype has the higher phenotypic expression in our Spanish Mediterranean population.
doi:10.1007/s00277-010-0901-9
PMCID: PMC2887936  PMID: 20107990
Iron overload; HFE gene; C282Y variant; H63D variant; S65C variant; Mediterranean diet
9.  Molecular basis of HFE-hemochromatosis 
Iron-overload disorders owing to genetic misregulation of iron acquisition are referred to as hereditary hemochromatosis (HH). The most prevalent genetic iron overload disorder in Caucasians is caused by mutations in the HFE gene, an atypical MHC class I molecule. Recent studies classified HFE/Hfe-HH as a liver disease with the primarily failure in the production of the liver iron hormone hepcidin in hepatocytes. Inadequate hepcidin expression signals for excessive iron absorption from the diet and iron deposition in tissues causing multiple organ damage and failure. This review focuses on the molecular actions of the HFE/Hfe and hepcidin in maintaining systemic iron homeostasis and approaches undertaken so far to combat iron overload in HFE/Hfe-HH. In the light of the recent investigations, novel roles of extra-hepatocytic Hfe are discussed raising a question to the relevance of the multipurpose functions of Hfe for the understanding of HH-associated pathologies.
doi:10.3389/fphar.2014.00042
PMCID: PMC3949417  PMID: 24653703
Hfe; HH; hepcidin; extra-hepatic Hfe; Bmp/Smad signaling
10.  Prevalence of H63D, S65C and C282Y hereditary hemochromatosis gene mutations in Slovenian population by an improved high-throughput genotyping assay 
BMC Medical Genetics  2007;8:69.
Background
Hereditary hemochromatosis (HH) is a common genetic disease characterized by excessive iron overload that leads to multi-organ failure. Although the most prevalent genotype in HH is homozygosity for C282Y mutation of the HFE gene, two additional mutations, H63D and S65C, appear to be associated with a milder form of HH. The aim of this study was to develop a high-throughput assay for HFE mutations screening based on TaqMan technology and to determine the frequencies of HFE mutations in the Slovenian population.
Methods
Altogether, 1282 randomly selected blood donors from different Slovenian regions and 21 HH patients were analyzed for the presence of HFE mutations by an in-house developed real-time PCR assay based on TaqMan technology using shorter non-interfering fluorescent single nucleotide polymorphism (SNP)-specific MGB probes. The assay was validated by RFLP analysis and DNA sequencing.
Results
The genotyping assay of the H63D, S65C and C282Y mutations in the HFE gene, based on TaqMan technology proved to be fast, reliable, with a high-throughput capability and 100% concordant with genotypes obtained by RFLP and DNA sequencing. The observed frequency of C282Y homozygotes in the group of HH patients was only 48%, others were of the heterogeneous HFE genotype. Among 1282 blood donors tested, the observed H63D, S65C and C282Y allele frequency were 12.8% (95% confidence interval (CI) 11.5 – 14.2%), 1.8% (95% CI 1.4 – 2.5%) and 3.6% (95% CI 3.0 – 4.5%), respectively. Approximately 33% of the tested subjects had at least one of the three HH mutations, and 1% of them were C282Y homozygotes or compound heterozygotes C282Y/H63D or C282Y/S65C, presenting an increased risk for iron overload disease. A significant variation in H63D allele frequency was observed for one of the Slovenian regions.
Conclusion
The improved real-time PCR assay for H63D, S65C and C282Y mutations detection is accurate, fast, cost-efficient and ready for routine screening and diagnostic procedures. The genotype frequencies in the Slovenian population agree with those reported for the Central European populations although some deviations where observed in comparison with other populations of Slavic origin. Regional distribution of the mutations should be considered when planning population screening.
doi:10.1186/1471-2350-8-69
PMCID: PMC2253505  PMID: 18036208
11.  Accuracy of Family History of Hemochromatosis or Iron Overload: The Hemochromatosis and Iron Overload Screening Study 
Background & Aims
The aim of this study was to assess the analytic validity of self-reported family history of hemochromatosis or iron overload.
Methods
A total of 141 probands, 549 family members, and 641 controls participated in the primary care Hemochromatosis and Iron Overload Screening Study. Participants received a postscreening clinical examination and completed questionnaires about personal and family histories of hemochromatosis or iron overload, arthritis, diabetes, liver disease, and heart disease. We evaluated sensitivities and specificities of proband-reported family history, and concordance of HFE genotype C282Y/C282Y in probands and siblings who reported having hemochromatosis or iron overload.
Results
The sensitivities of proband-reported family history ranged from 81.4% for hemochromatosis or iron overload to 18.4% for liver disease; specificities for diabetes, liver disease, and heart disease were greater than 94%. Hemochromatosis or iron overload was associated with a positive family history across all racial/ethnic groups in the study (odds ratio, 14.53; 95% confidence intervals, 7.41–28.49; P < .0001) and among Caucasians (odds ratio, 16.98; 95% confidence intervals, 7.53–38.32; P < .0001). There was 100% concordance of HFE genotype C282Y/C282Y in 6 probands and 8 of their siblings who reported having hemochromatosis or iron overload.
Conclusions
Self-reported family history of hemochromatosis or iron overload can be used to identify individuals whose risk of hemochromatosis or iron overload and associated conditions is increased. These individuals could benefit from further evaluation with iron phenotyping and HFE mutation analysis.
doi:10.1016/j.cgh.2008.04.003
PMCID: PMC3779058  PMID: 18585964
12.  Molecular and clinical correlates in iron overload associated with mutations in ferroportin 
Haematologica  2006;91(8):1092-1095.
Mutations in ferroportin (Fpn) result in iron overload. We correlate the behavior of three Fpn mutants in vitro with patients’ phenotypes. Patients with Fpn mutations A77D or N174I showed macrophage iron loading. In cultured cells, FpnA77D did not reach the cell surface and cells did not export iron. Fpn mutant N174I showed plasma membrane and intracellular localization, and did not transport iron. Fpn mutation G80S was targeted to the cell surface and was transport competent, however patients showed macrophage iron. We suggest that FpnG80S represents a class of Fpn mutants whose behavior in vitro does not explain the patients’ phenotype.
PMCID: PMC3718284  PMID: 16885049
ferroportin; hemochromatosis; hepcidin; iron transport
13.  Altered hepatic BMP signaling pathway in human HFE hemochromatosis 
Blood cells, molecules & diseases  2010;45(4):308-312.
Human hemochromatosis (HC) has been associated with the common C282Y polymorphism of HFE or rare pathogenic mutations of TfR2, HJV, FPN and HAMP. All forms of human HC seem to be caused by low or inadequate levels of hepcidin, the iron hormone. We and others have recently shown that Hfe−/−mice exhibit an impairment in the bone morphogenetic protein (BMP) signaling pathway controlling hepcidin. However, all data indicating the central role of BMPs in hepcidin regulation and an impaired BMP/SMAD signaling in HC have been collected in mice. In this study we investigated whether also in humans the expression of BMP signaling targets, SMAD7 and Id1, are associated with liver iron concentration (LIC) and whether such regulation is disrupted in HFE-HC. We correlated the mRNA expression, assessed by RT-PCR, of HAMP, SMAD7 and Id1 with LIC in liver biopsies from patients with normal iron status, HFE-HC or non-HC hepatic iron overload. We found that in human liver, not only HAMP, but also SMAD7 and Id1 mRNA significantly correlate with the extent of hepatic iron burden. However, this correlation is lost in patients with HFE-HC, but maintained in subjects with non-hemochromatotic iron overload. These data indicate that in human HFE-HC a disrupted BMP/SMAD signaling in the liver is key in the pathogenesis of the disease.
doi:10.1016/j.bcmd.2010.08.010
PMCID: PMC3295241  PMID: 20863724
iron overload; bone morphogenetic proteins; hepcidin; SMAD proteins
14.  Hepcidin and Ferroportin: The New Players in Iron Metabolism 
Seminars in liver disease  2011;31(3):272-279.
Systemic iron homeostasis is regulated by the interaction of the peptide hormone, hepcidin and the iron exporter, ferroportin. Mutations in FPN1, the gene that encodes ferroportin, result in iron-overload disease that shows dominant inheritance and variation in phenotype. The inheritance of ferroportin-linked disorders can be explained by the finding that ferroportin is a multimer and the product of the mutant allele participates in multimer formation. The nature of the ferroportin mutant can explain the variation in phenotype, which is due to either decreased iron export activity or decreased ability to be downregulated by hepcidin. Iron export through ferroportin is determined by the concentration of ferroportin in plasma membrane, which is the result of both synthetic and degradation events. Ferroportin degradation can occur by hepcidin-dependent and hepcidin-independent internalization. Ferroportin expression is regulated transcriptionally and posttranslationally.
doi:10.1055/s-0031-1286058
PMCID: PMC3706197  PMID: 21901657
Ferroportin; iron; hepcidin; genetics
15.  Frequency of Two Common HFE Gene Mutations (C282Y and H63D) in a Group of Iranian Patients With Cryptogenic Cirrhosis 
Hepatitis Monthly  2011;11(11):887-889.
Background
The human HFE gene (a key component of iron homeostasis in humans) is involved in hereditary hemochromatosis, a common autosomal recessive genetic disorder that is characterized by excessive intestinal iron absorption and progressive iron overload.
Objectives
In this study, we assessed the frequency of two common forms of hemochromatosis HFE gene mutation (C282Y and H63D) in patients suffering from cryptogenic cirrhosis.
Patients and Methods
One hundred and fifty individuals were included in this study, in which 100 were patients with cryptogenic cirrhosis and 50 were from the normal population. All individuals were examined for common HFE gene mutations by amplification of nucleotide 845 C282Y and 187 H63D alleles and product analysis using the polymerase chain reaction method and restriction enzyme digestion.
Results
No case of either a homozygous or heterozygous C282Y mutation was found. For the H63D mutation, no homozygosity was detected but heterozygosity was detected in 22% of patients and in 28% of the normal population.
Conclusions
Hereditary hemochromatosis is not a major cause of cryptogenic cirrhosis in the Iranian population.
doi:10.5812/kowsar.1735143x.781
PMCID: PMC3269056  PMID: 22308152
Mutation; Iran; Liver Cirrhosis; Genes
16.  The Role of Ubiquitination in Hepcidin-Independent and Hepcidin-Dependent Degradation of Ferroportin 
Cell metabolism  2011;14(5):635-646.
SUMMARY
The iron exporter ferroportin (Fpn) is essential to transfer iron from cells to plasma. Systemic iron homeostasis in vertebrates is regulated by the hepcidin-mediated internalization of Fpn. Here we demonstrate a second route for Fpn internalization, when cytosolic iron levels are low Fpn is internalized in a hepcidin-independent manner dependent upon the E3 ubiquitin ligase Nedd4-2 and the Nedd4-2 binding protein Nfdip-1. Retention of cell surface Fpn through reductions in Nedd4-2 results in cell death through depletion of cytosolic iron. Nedd4-2 is also required for internalization of Fpn in the absence of ferroxidase activity as well as for the entry of hepcidin-induced Fpn into the multivesicular body. C. elegans lacks hepcidin genes and C. elegans Fpn expressed in mammalian cells is not internalized by hepcidin but is internalized in response to iron deprivation in a Nedd4-2-dependent manner supporting the hypothesis that Nedd4-2-induced internalization of Fpn is evolutionarily conserved.
doi:10.1016/j.cmet.2011.09.008
PMCID: PMC3229915  PMID: 22019085
17.  Hepcidin and HFE protein: Iron metabolism as a target for the anemia of chronic kidney disease 
World Journal of Nephrology  2012;1(6):166-176.
The anemia of chronic kidney disease and hemodialysis is characterized by chronic inflammation and release of cytokines, resulting in the upregulation of the iron hormone hepcidin, also increased by iron therapy and reduced glomerular filtration, with consequent reduction in iron absorption, recycling, and availability to the erythron. This response proves advantageous in the short-term to restrain iron availability to pathogens, but ultimately leads to severe anemia, and impairs the response to erythropoietin (Epo) and iron. Homozygosity for the common C282Y and H63D HFE polymorphisms influence iron metabolism by hampering hepcidin release by hepatocytes in response to increased iron stores, thereby resulting in inadequate inhibition of the activity of Ferroportin-1, inappropriately high iron absorption and recycling, and iron overload. However, in hemodialysis patients, carriage of HFE mutations may confer an adaptive benefit by decreasing hepcidin release in response to iron infusion and inflammation, thereby improving iron availability to erythropoiesis, anemia control, the response to Epo, and possibly survival. Therefore, anti-hepcidin therapies may improve anemia management in hemodialysis. However, HFE mutations directly favor hemoglobinization independently of hepcidin, and reduce macrophages activation in response to inflammation, whereas hepcidin might also play a beneficial anti-inflammatory and anti-microbic action during sepsis, so that direct inhibition of HFE-mediated regulation of iron metabolism may represent a valuable alternative therapeutic target. Genetic studies may offer a valuable tool to test these hypotheses and guide the research of new therapies.
doi:10.5527/wjn.v1.i6.166
PMCID: PMC3782218  PMID: 24175256
Chronic kidney disease; Hemodialysis; Iron; HFE protein; Iron overload
18.  The global burden of iron overload 
Hepatology International  2009;3(3):434-444.
There have been major developments in the field of iron metabolism in the past decade following the identification of the HFE gene and the mutation responsible for the C282Y substitution in the HFE protein. While HFE-associated hemochromatosis occurs predominantly in people of northern European extraction, other less-common mutations can lead to the same clinical syndrome and these may occur in other populations in the Asian-Pacific region. The most common of these is the mutation that leads to changes in the ferroportin molecule, the protein responsible for the transport of iron across the basolateral membrane of the enterocyte and from macrophages. Recent research has unraveled the molecular processes of iron transport and regulation of how these are disturbed in hemochromatosis and other iron-loading disorders. At the same time, at least one new oral iron chelating agent has been developed that shows promise in the therapy of hemochromatosis as well as thalassemia and other secondary causes of iron overload. It is pertinent therefore to examine the developments in the global field of iron overload that have provided insights into the pathogenesis, disease penetrance, comorbid factors, and management.
doi:10.1007/s12072-009-9144-z
PMCID: PMC2748371  PMID: 19669241
Haemochromatosis; Iron metabolism; HFE haemochromatosis; Secondary iron overload
19.  Role of Ferroportin in Macrophage-Mediated Immunity▿  
Infection and Immunity  2010;78(12):5099-5106.
Perturbations in iron metabolism have been shown to dramatically impact host response to infection. The most common inherited iron overload disorder results from defects in the HFE gene product, a major histocompatibility complex class I-like protein that interacts with transferrin receptors. HFE-associated hemochromatosis is characterized by abnormally high levels of the iron efflux protein ferroportin. In this study, J774 murine macrophages overexpressing ferroportin were used to investigate the influence of iron metabolism on the release of nitric oxide (NO) in response to infection. Overexpression of ferroportin significantly impaired intracellular Mycobacterium tuberculosis growth during early stages of infection. When challenged with lipopolysaccharide (LPS) or M. tuberculosis infection, control macrophages increased NO synthesis, but macrophages overexpressing ferroportin had significantly impaired NO production in response to LPS or M. tuberculosis. Increased NO synthesis in control cells was accompanied by increased iNOS mRNA and protein, while upregulation of iNOS protein was markedly reduced when J744 cells overexpressing ferroportin were challenged with LPS or M. tuberculosis, thus limiting the bactericidal activity of these macrophages. The proinflammatory cytokine gamma interferon reversed the inhibitory effect of ferroportin overexpression on NO production. These results suggest a novel role for ferroportin in attenuating macrophage-mediated immune responses.
doi:10.1128/IAI.00498-10
PMCID: PMC2981308  PMID: 20837712
20.  Duodenal mRNA expression of iron related genes in response to iron loading and iron deficiency in four strains of mice 
Gut  2002;51(5):648-653.
Background: Although much progress has been made recently in characterising the proteins involved in duodenal iron trafficking, regulation of intestinal iron transport remains poorly understood. It is not known whether the level of mRNA expression of these recently described molecules is genetically regulated. This is of particular interest however as genetic factors are likely to determine differences in iron status among mouse strains and probably also contribute to the phenotypic variability seen with disruption of the haemochromatosis gene.
Aims: To investigate this issue, we examined concomitant variations in duodenal cytochrome b (Dcytb), divalent metal transporter 1 (DMT1), ferroportin 1 (FPN1), hephaestin, stimulator of Fe transport (SFT), HFE, and transferrin receptor 1 (TfR1) transcripts in response to different dietary iron contents in the four mouse strains C57BL/6, DBA/2, CBA, and 129/Sv.
Subjects: Six mice of each strain were fed normal levels of dietary iron, six were subjected to the same diet supplemented with 2% carbonyl iron, and six were fed an iron deficient diet.
Methods: Quantification of mRNAs isolated from the duodenum was performed using real time reverse transcription-polymerase chain reaction.
Results: There was a significant increase in mRNA expression of Dcytb, DMT1, FPN1, and TfR1 when mice were fed an iron deficient diet, and a significant decrease in mRNA expression of these molecules when mice were fed an iron supplemented diet. Strain to strain differences were observed not only in serum transferrin saturations, with C57BL/6 mice having the lowest values, but also in hepatic iron stores and in duodenal mRNA expression of Dcytb, DMT1, FPN1, hephaestin, HFE, and TfR1.
Conclusions: The results favour some degree of genetic control of mRNA levels of these molecules.
PMCID: PMC1773425  PMID: 12377801
iron metabolism; duodenal iron absorption; dietary iron content; mRNA
21.  Expression and Function of Iron-Regulatory Proteins in Retina 
IUBMB life  2010;62(5):363-370.
Summary
Iron is essential for cell survival and function; yet excess iron is toxic to cells. Therefore, the cellular and whole-body levels of iron are regulated exquisitely. At least a dozen proteins participate in the regulation of iron homeostasis. Hemochromatosis, a genetic disorder of iron overload, is caused by mutations in at least five genes, namely HFE, hemojuvelin, Transferrin receptor 2, ferroportin, and hepcidin. Retina is separated from systemic circulation by inner and outer blood-retinal barriers; therefore it is widely believed that this tissue is immune to changes in systemic circulation. Even though hemochromatosis is associated with iron overload and dysfunction of a variety of systemic organs, little is known on the effects of this disease on the retina. Recent studies have shown that all five genes that are associated with hemochromatosis are expressed in the retina in a cell type-specific manner. The retinal pigment epithelium, which forms the outer blood-retinal barrier, expresses all of these five genes. It is therefore clearly evident that iron homeostasis in the retina is maintained locally by active participation of various iron-regulatory proteins. Excess iron is detrimental to the retina as evidenced from human studies and from mouse models of iron overload. Retinal iron homeostasis is disrupted in various clinical conditions such as hemochromatosis, aceruloplasminemia, age-related macular degeneration, and bacterial and viral infections.
doi:10.1002/iub.326
PMCID: PMC3789380  PMID: 20408179
Hemochromatosis; age-related macular degeneration; iron toxicity; oxidative damage; retina
22.  Telomere length and elevated iron: The influence of phenotype and HFE genotype 
American journal of hematology  2013;88(6):492-496.
Elevated body iron stores are associated with morbidity and mortality due to oxidative stress. Hereditary hemochromatosis, a common condition caused by HFE gene mutations, can lead to excess iron storage and disease but clinical penetrance of HFE gene mutations is low and many people with elevated iron stores lack HFE mutations. We analyzed data from the Hemochromatosis and Iron Overload Screening Study to assess the relationship among HFE genotype (individuals with either homozygous or compound heterozygous status for C282Y and/or H63D HFE mutations were defined as genotype positive, or G+), elevated iron phenotype (individuals exceeding gender-specific transferrin saturation and serum ferritin threshold levels were considered phenotype positive, or P+), and leukocyte telomere length, a marker of biological aging and cumulative oxidative stress. In unadjusted analyses in comparison to individuals who were G−P−, G+P− were not significantly different (OR 0.74; 95% CI 0.26–2.04), while the G+P+ (OR 2.03; 95% CI 1.15–3.56), and G−P+ (OR 2.24; 95% CI 1.5–3.29) had increased risk of short telomeres (<=25th percentile) rather than long telomeres (>=75th percentile). In analyses adjusting for age, gender, and race/ethnicity, the effect of individuals with elevated iron phenotypes having short telomeres persisted with G+P+ individuals (OR 1.94; 95% CI 1.02–3.72), and G−P+ individuals (OR 2.17; 95% CI 1.39–3.39) being significantly different from the G−P− group. In conclusion, elevated iron phenotype, but not HFE genotype, was associated with shortened telomeres. Further studies will be needed to determine whether telomere length provides a marker for morbidities specifically associated with iron overload.
doi:10.1002/ajh.23438
PMCID: PMC3784668  PMID: 23512844
23.  Pathophysiology of Hereditary Hemochromatosis 
Seminars in liver disease  2005;25(4):411-419.
Hereditary hemochromatosis (HH) encompasses several inherited disorders of iron homeostasis characterized by increased gastrointestinal iron absorption and tissue iron deposition. The most common form of this disorder is HFE-related HH, nearly always caused by homozygosity for the C282Y mutation. A substantial proportion of C282Y homozygotes do not develop clinically significant iron overload, suggesting roles for environmental factors and modifier genes in determining the phenotype. Recent studies have demonstrated that the pathogenesis of nearly all forms of HH involves inappropriately decreased expression of the iron-regulatory hormone hepcidin. Hepcidin serves to decrease the export of iron from reticuloendothelial cells and absorptive enterocytes. Thus, HH patients demonstrate increased iron release from these cell types, elevated circulating iron, and iron deposition in vulnerable tissues. The mechanism by which HFE influences hepcidin expression is an area of current investigation and may offer insights into the phenotypic variability observed in persons with mutations in HFE.
doi:10.1055/s-2005-923313
PMCID: PMC2587012  PMID: 16315135
Hemochromatosis; iron; HFE; hepcidin; ferroportin
24.  Iron in Skin of Mice with Three Etiologies of Systemic Iron Overload 
In human hemochromatosis, tissue toxicity is a function of tissue iron levels. Despite reports of skin toxicity in hemochromatosis, little is known about iron levels in skin of individuals with systemic iron overload. We measured skin iron and studied skin histology in three mouse models of systemic iron overload: mice with a deletion of the hemochromatosis (Hfe) gene, mice fed a high iron diet, and mice given parenteral injections of iron. In Hfe−/− mice, iron content in the epidermis and dermis was unexpectedly the same as in Hfe+/+ mice, and there were no histological abnormalities detected after 30 wk. A high iron diet produced increased iron in the epidermis of both normal and Hfe−/− animals; a high diet increased iron in the dermis only in Hfe−/− mice. Increased skin iron was not associated with other histological changes, even after 19 wk. Parenteral administration of iron produced increased iron in the epidermis and dermis, and gave the skin a bronze hue. These results show that the amount and distribution of iron in the skin depends on the etiology of iron overload. It appears that neither Hfe deletion nor elevated skin iron alone can account for cutaneous manifestations reportedly seen in humans with hereditary hemochromatosis.
doi:10.1111/j.0022-202X.2005.23949.x
PMCID: PMC2243217  PMID: 16354190
hemochromatosis; skin; iron; diet; ferritin
25.  Hereditary Hemochromatosis and Transferrin Receptor 2 
Biochimica et Biophysica Acta  2011;1820(3):256-263.
Background
Multicellular organisms regulate the uptake of calories, trace elements, and other nutrients by complex feedback mechanisms. In the case of iron, the body senses internal iron stores, iron requirements for hematopoiesis, and inflammatory status, and regulates iron uptake by modulating the uptake of dietary iron from the intestine. Both the liver and the intestine participate in the coordination of iron uptake and distribution in the body. The liver senses inflammatory signals and iron status of the organism and secretes a peptide hormone, hepcidin. Under high iron or inflammatory conditions hepcidin levels increase. Hepcidin binds to the iron transport protein, ferroportin (FPN), promoting FPN internalization and degradation. Decreased FPN levels reduce iron efflux out of intestinal epithelial cells and macrophages into the circulation. Derangements in iron metabolism result in either the abnormal accumulation of iron in the body, or in anemias. The identification of the mutations that cause the iron overload disease, hereditary hemochromatosis (HH), or iron-refractory iron-deficiencey anemia has revealed many of the proteins used to regulate iron uptake.
Scope of the review
In this review we discuss recent data concerning the regulation of iron homeostasis in the body by the liver and how transferrin receptor 2 (TfR2) affects this process.
Major conclusions
TfR2 plays a key role in regulating iron homeostasis in the body.
General significance
The regulation of iron homeostasis is important. One third of the people in the world are anemic. HH is the most common inherited disease in people of Northern European origin and can lead to severe health complications if left untreated.
doi:10.1016/j.bbagen.2011.07.015
PMCID: PMC3234335  PMID: 21864651
Hereditary hemochromatosis; transferrin receptor 2; TfR2; HFE; hepcidin; hemojuvelin; BMP; ferroportin

Results 1-25 (422962)