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1.
Clin Gastroenterol Hepatol ; 18(7): 1584-1591, 2020 06.
Article in English | MEDLINE | ID: mdl-31628998

ABSTRACT

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is common and related to obesity and insulin resistance. Iron metabolism is impaired in obese individuals and iron deficiency has been associated with physical inactivity. We investigated whether iron bioavailability is reduced in patients with NAFLD and contributes to reduced cardiorespiratory fitness. METHODS: We collected information on weight-adjusted, submaximal physical work capacity (PWC), ultrasound-determined hepatic steatosis, iron indices, and hematologic and metabolic parameters from 390 female and 458 male participants of the Raine Study-a longitudinal study of disease development in 2868 children in Western Australia. X2 and linear regression analyses were used to compare characteristics of study participants according to NAFLD status at age 17 years. RESULTS: Fourteen percent of the cohort had NAFLD. PWC was significantly reduced in adolescents with NAFLD compared to adolescents without NAFLD (reduction of 0.17 W/kg, P = .0003, adjusted for sex and body mass index [BMI]). Iron bioavailability (assessed by mean corpuscular volume [MCV], mean corpuscular haemoglobin [MCH], transferrin saturation, and serum levels of iron) was inversely correlated with BMI in adolescents with NAFLD (P ≤ .01 for all, adjusted for sex) but not in adolescents without NAFLD (P > .30). MCV and MCH correlated with PWC (MCV, P = .002 for female and P = .0003 male participants; MCH, P = .004 for female and P = .01 for male participants), irrespective of NAFLD status. Reduced PWC was associated with lower transferrin saturation in adolescents with NAFLD (reduction of 0.012 W/kg per unit decrease in transferrin saturation, P = .007) but not in adolescents without NAFLD (reduction of 0.001 W/kg, P = .40), adjusted for sex. This association was independent of MCV or MCH. CONCLUSIONS: In a well-defined cohort of adolescents, we found NAFLD to be associated with decreased cardiorespiratory fitness, independent of BMI. The relationship between transferrin saturation and PWC in adolescents with NAFLD indicates that functional iron deficiency might contribute to reductions in cardiorespiratory fitness.


Subject(s)
Non-alcoholic Fatty Liver Disease , Adolescent , Body Mass Index , Child , Female , Humans , Iron , Liver , Longitudinal Studies , Male , Obesity
2.
Blood Cells Mol Dis ; 74: 18-24, 2019 02.
Article in English | MEDLINE | ID: mdl-30340937

ABSTRACT

Detection of HFE Haemochromatosis (HH) is challenging in the absence of clinical features. HH subjects have elevated erythrocyte parameters compared to those without HH, but it remains unclear how this could be applied in clinical practice. Thus, we determined the sensitivity, specificity and clinical utility of erythrocyte parameters in 144 HH subjects with (n = 122) or without (n = 22) clinical and/or biochemical expression of iron overload, 1844 general population controls, and 700 chronic disease subjects. For both expressing and non-expressing HH subjects, the mean pre- and post-phlebotomy values of mean cell volume (MCV) and mean cell haemoglobin (MCH) were always significantly higher when compared to all other groups and demonstrated excellent diagnostic utility for detection of HH in men and women (AUROC 0.83-0.9; maximal sensitivity and specificity 82% and 78%) using cut-off values for MCV >91 fL or MCH >31 pg, respectively. Between 34 and 62% of all HH subjects would be detected, and <4% of all non-HH subjects would undergo unnecessary testing, if those with MCV or MCH values >94 fL or 32.2 pg, respectively, were evaluated.


Subject(s)
Erythrocyte Indices , Hemochromatosis Protein , Hemochromatosis/diagnosis , Adult , Aged , Case-Control Studies , Female , Hematologic Tests , Hemochromatosis/blood , Hemoglobins/analysis , Humans , Iron Overload , Male , Middle Aged , Sensitivity and Specificity
3.
BMC Cancer ; 18(1): 863, 2018 Sep 03.
Article in English | MEDLINE | ID: mdl-30176879

ABSTRACT

BACKGROUND: Cancer risk is associated with serum iron levels. The aim of this study was to evaluate whether haematological parameters reflect serum iron levels and may also be associated with cancer risk. METHODS: We studied 1564 men and 1769 women who were enrolled in the Busselton Health Study, Western Australia. Haematological parameters evaluated included haemoglobin (Hb), mean cell volume (MCV), mean cell haemoglobin (MCH) and mean cell haemoglobin concentration (MCHC) and red cell distribution width (RCDW). Statistical analyses included t-tests for quantitative variables, chi-square tests for categorical variables and Cox proportional hazards regression modelling for cancer incidence and death. RESULTS: There was marginal evidence of an association between MCV (as a continuous variable) and non-skin cancer incidence in women (HR 1.15, 95% CI 1.013, 1.302; p = 0.030) but the hazard ratio was attenuated to non-significance after adjustment for serum ferritin (SF), iron and transferrin saturation (TS) (HR 1.11, 95% CI 0.972, 1.264; p = 0.126). There was strong evidence of an association between MCHC and prostate cancer incidence in men; the estimated hazard ratio for an increase of one SD (0.5) in MCHC was 1.27 (95% CI 1.064, 1.507; p = 0.008). These results remained significant after further adjustment for SF and iron; the estimated hazard ratio for an increase of one SD (0.5) in MCHC was 1.25 (p = 0.014, 95% CI 1.05 to 1.48). CONCLUSIONS: The MCHC and MCV were associated with cancer incidence in a Western Australian population, although only MCHC remained associated with prostate cancer after adjusting with serum iron and TS (circulating iron) and SF (storage iron). Haematological parameters are thus of limited utility in population profiling for future cancer risk.


Subject(s)
Erythrocyte Indices , Hemoglobins/metabolism , Iron/blood , Neoplasms/blood , Adult , Aged , Australia/epidemiology , Blood Cell Count , Female , Ferritins/blood , Hemoglobins/isolation & purification , Humans , Male , Middle Aged , Neoplasms/classification , Neoplasms/mortality , Neoplasms/pathology , Proportional Hazards Models , Risk Factors
4.
Rare Dis ; 4(1): e1198458, 2016.
Article in English | MEDLINE | ID: mdl-27500074

ABSTRACT

We previously demonstrated elevated brain iron levels in myelinated structures and associated cells in a hemochromatosis Hfe (-/-) xTfr2 (mut) mouse model. This was accompanied by altered expression of a group of myelin-related genes, including a suite of genes causatively linked to the rare disease family 'neurodegeneration with brain iron accumulation' (NBIA). Expanded data mining and ontological analyses have now identified additional myelin-related transcriptome changes in response to brain iron loading. Concordance between the mouse transcriptome changes and human myelin-related gene expression networks in normal and NBIA basal ganglia testifies to potential clinical relevance. These analyses implicate, among others, genes linked to various rare central hypomyelinating leukodystrophies and peripheral neuropathies including Pelizaeus-Merzbacher-like disease and Charcot-Marie-Tooth disease as well as genes linked to other rare neurological diseases such as Niemann-Pick disease. The findings may help understand interrelationships of iron and myelin in more common conditions such as hemochromatosis, multiple sclerosis and various psychiatric disorders.

5.
Am J Clin Nutr ; 104(3): 736-42, 2016 09.
Article in English | MEDLINE | ID: mdl-27488234

ABSTRACT

BACKGROUND: Although the carcinogenic potential of iron has been shown, evidence from observational studies that have linked serum iron variables and cancer outcomes has been inconsistent. OBJECTIVE: We investigated whether higher iron concentrations increased risk of cancer outcomes. DESIGN: A prospective examination of iron biomarkers as independent risk factors for cancer was assessed in 1597 men and 1795 women aged 25-79 y who participated in the 1994/1995 Busselton Health Survey and had relevant data, no history of cancer before the survey, and serum ferritin concentrations ≥20 µg/L. Follow-up for incident cancers and death from cancer was available to 2010. Proportional hazards regression modeling was performed to investigate if iron status predicted cancer incidence and mortality. RESULTS: After adjustments for age, smoking, drinking, anthropometric and biochemical variables, or menopausal status (breast cancer), higher serum iron concentrations and transferrin saturation were associated with increased risks of incident nonskin cancer [HR for iron: 1.83 (95% CI: 1.21, 2.76; P < 0.01); HR for transferrin saturation: 1.68 (95% CI: 1.18, 2.38; P < 0.01)] including breast cancer [HR for iron: 2.45 (95% CI:1.12, 5.34; P < 0.05); HR for transferrin saturation: 1.90 (95% CI:1.02, 3.56; P < 0.05)] in women. Transferrin saturation was also associated with a greater risk of cancer death (HR: 2.48; 95% CI: 1.28, 4.82; P < 0.01). In men, higher iron concentrations were associated with reduced risks of incident nonskin cancer (HR: 0.65; 95% CI: 0.42, 0.99; P < 0.05) including colorectal cancer (HR: 0.34; 95% CI: 0.12, 0.95; P < 0.05). There was no association between serum iron and colorectal cancer risk in women. Serum ferritin was not associated with cancer risk or cancer death. CONCLUSIONS: Higher transferrin saturation or serum iron concentrations were associated with increased nonskin cancer risk and increased risk of cancer death. Conversely, in men, higher serum iron concentrations were associated with decreased risk of nonskin cancer. The molecular basis for the observed differences in the association between serum iron and nonskin cancer risk is unclear.


Subject(s)
Breast Neoplasms/blood , Colorectal Neoplasms/blood , Iron/blood , Transferrin/analysis , Adult , Aged , Biomarkers/blood , Breast Neoplasms/diagnosis , Breast Neoplasms/epidemiology , Breast Neoplasms/mortality , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/mortality , Female , Ferritins/blood , Follow-Up Studies , Health Surveys , Humans , Incidence , Iron/metabolism , Male , Middle Aged , Prognosis , Proportional Hazards Models , Prospective Studies , Risk Factors , Sex Factors , Transferrin/metabolism , Treatment Outcome , Western Australia/epidemiology
6.
Biochim Biophys Acta ; 1863(4): 727-48, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26844773

ABSTRACT

Essential metals, such as iron and copper, play a critical role in a plethora of cellular processes including cell growth and proliferation. However, concomitantly, excess of these metal ions in the body can have deleterious effects due to their ability to generate cytotoxic reactive oxygen species (ROS). Thus, the human body has evolved a very well-orchestrated metabolic system that keeps tight control on the levels of these metal ions. Considering their very high proliferation rate, cancer cells require a high abundance of these metals compared to their normal counterparts. Interestingly, new anti-cancer agents that take advantage of the sensitivity of cancer cells to metal sequestration and their susceptibility to ROS have been developed. These ligands can avidly bind metal ions to form redox active metal complexes, which lead to generation of cytotoxic ROS. Furthermore, these agents also act as potent metastasis suppressors due to their ability to up-regulate the metastasis suppressor gene, N-myc downstream regulated gene 1. This review discusses the importance of iron and copper in the metabolism and progression of cancer, how they can be exploited to target tumors and the clinical translation of novel anti-cancer chemotherapeutics.


Subject(s)
Antineoplastic Agents , Chelating Agents , Copper/metabolism , Drug Discovery , Iron/metabolism , Metals/metabolism , Animals , Antineoplastic Agents/therapeutic use , Chelating Agents/therapeutic use , Drug Discovery/methods , Drug Discovery/trends , Humans , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Oxidation-Reduction , Reactive Oxygen Species/metabolism
7.
PLoS One ; 8(11): e78850, 2013.
Article in English | MEDLINE | ID: mdl-24223168

ABSTRACT

Chronic intestinal inflammation and high dietary iron are associated with colorectal cancer development. The role of Stat3 activation in iron-induced colonic inflammation and tumorigenesis was investigated in a mouse model of inflammation-associated colorectal cancer. Mice, fed either an iron-supplemented or control diet, were treated with azoxymethane and dextran sodium sulfate (DSS). Intestinal inflammation and tumor development were assessed by endoscopy and histology, gene expression by real-time PCR, Stat3 phosphorylation by immunoblot, cytokines by ELISA and apoptosis by TUNEL assay. Colonic inflammation was more severe in mice fed an iron-supplemented compared with a control diet one week post-DSS treatment, with enhanced colonic IL-6 and IL-11 release and Stat3 phosphorylation. Both IL-6 and ferritin, the iron storage protein, co-localized with macrophages suggesting iron may act directly on IL-6 producing-macrophages. Iron increased DSS-induced colonic epithelial cell proliferation and apoptosis consistent with enhanced mucosal damage. DSS-treated mice developed anemia that was not alleviated by dietary iron supplementation. Six weeks post-DSS treatment, iron-supplemented mice developed more and larger colonic tumors compared with control mice. Intratumoral IL-6 and IL-11 expression increased in DSS-treated mice and IL-6, and possibly IL-11, were enhanced by dietary iron. Gene expression of iron importers, divalent metal transporter 1 and transferrin receptor 1, increased and iron exporter, ferroportin, decreased in colonic tumors suggesting increased iron uptake. Dietary iron and colonic inflammation synergistically activated colonic IL-6/IL-11-Stat3 signaling promoting tumorigenesis. Oral iron therapy may be detrimental in inflammatory bowel disease since it may exacerbate colonic inflammation and increase colorectal cancer risk.


Subject(s)
Colitis/metabolism , Colonic Neoplasms/metabolism , Interleukin-11/metabolism , Interleukin-6/metabolism , STAT3 Transcription Factor/metabolism , Signal Transduction , Animals , Apoptosis/drug effects , Cation Transport Proteins/genetics , Cation Transport Proteins/metabolism , Cell Proliferation/drug effects , Colitis/chemically induced , Colitis/genetics , Colonic Neoplasms/genetics , Dextran Sulfate/toxicity , Enzyme-Linked Immunosorbent Assay , Female , Gene Expression Regulation, Neoplastic , Immunoblotting , In Situ Nick-End Labeling , Interleukin-11/genetics , Interleukin-6/genetics , Iron, Dietary/adverse effects , Mice , Mice, Inbred C57BL , Phosphorylation/drug effects , Receptors, Transferrin/genetics , Receptors, Transferrin/metabolism , Reverse Transcriptase Polymerase Chain Reaction
8.
Hepatology ; 56(2): 585-93, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22383097

ABSTRACT

UNLABELLED: Mutations in hemochromatosis protein (HFE) or transferrin receptor 2 (TFR2) cause hereditary hemochromatosis (HH) by impeding production of the liver iron-regulatory hormone, hepcidin (HAMP). This study examined the effects of disruption of Hfe or Tfr2, either alone or together, on liver iron loading and injury in mouse models of HH. Iron status was determined in Hfe knockout (Hfe(-/-)), Tfr2 Y245X mutant (Tfr2(mut)), and double-mutant (Hfe(-/-) ×Tfr2(mut) ) mice by measuring plasma and liver iron levels. Plasma alanine transaminase (ALT) activity, liver histology, and collagen deposition were evaluated to assess liver injury. Hepatic oxidative stress was assessed by measuring superoxide dismutase (SOD) activity and F(2)-isoprostane levels. Gene expression was measured by real-time polymerase chain reaction. Hfe(-/-) ×Tfr2(mut) mice had elevated hepatic iron with a periportal distribution and increased plasma iron, transferrin saturation, and non-transferrin-bound iron, compared with Hfe(-/-), Tfr2(mut), and wild-type (WT) mice. Hamp1 expression was reduced to 40% (Hfe(-/-) and Tfr2(mut) ) and 1% (Hfe(-/-) ×Tfr2(mut)) of WT values. Hfe(-/-) ×Tfr2(mut) mice had elevated plasma ALT activity and mild hepatic inflammation with scattered aggregates of infiltrating inflammatory cluster of differentiation 45 (CD45)-positive cells. Increased hepatic hydoxyproline levels as well as Sirius red and Masson's Trichrome staining demonstrated advanced portal collagen deposition. Hfe(-/-) and Tfr2(mut) mice had less hepatic inflammation and collagen deposition. Liver F(2) -isoprostane levels were elevated, and copper/zinc and manganese SOD activities decreased in Hfe(-/-) ×Tfr2(mut), Tfr2(mut), and Hfe(-/-) mice, compared with WT mice. CONCLUSION: Disruption of both Hfe and Tfr2 caused more severe hepatic iron overload with more advanced lipid peroxidation, inflammation, and portal fibrosis than was observed with the disruption of either gene alone. The Hfe(-/-) ×Tfr2(mut) mouse model of iron-induced liver injury reflects the liver injury phenotype observed in human HH.


Subject(s)
Histocompatibility Antigens Class I/metabolism , Iron Overload , Liver Diseases , Membrane Proteins/metabolism , Receptors, Transferrin/metabolism , Alanine Transaminase/blood , Animals , Antimicrobial Cationic Peptides/genetics , Bone Morphogenetic Protein 6/genetics , Collagen/metabolism , Disease Models, Animal , Gene Expression/physiology , Hemochromatosis Protein , Hepcidins , Histocompatibility Antigens Class I/genetics , Inhibitor of Differentiation Protein 1/genetics , Iron/blood , Iron Overload/genetics , Iron Overload/metabolism , Iron Overload/pathology , Liver/pathology , Liver/physiology , Liver Diseases/genetics , Liver Diseases/metabolism , Liver Diseases/pathology , Membrane Proteins/genetics , Mice , Mice, Mutant Strains , Phenotype , Receptors, Transferrin/genetics
10.
Hepatology ; 52(2): 462-71, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20683946

ABSTRACT

UNLABELLED: Iron and cholesterol are both essential metabolites in mammalian systems, and too much or too little of either can have serious clinical consequences. In addition, both have been associated with steatosis and its progression, contributing, inter alia, to an increase in hepatic oxidative stress. The interaction between iron and cholesterol is unclear, with no consistent evidence emerging with respect to changes in plasma cholesterol on the basis of iron status. We sought to clarify the role of iron in lipid metabolism by studying the effects of iron status on hepatic cholesterol synthesis in mice with differing iron status. Transcripts of seven enzymes in the cholesterol biosynthesis pathway were significantly up-regulated with increasing hepatic iron (R(2) between 0.602 and 0.164), including those of the rate-limiting enzyme, 3-hydroxy-3-methylglutarate-coenzyme A reductase (Hmgcr; R(2) = 0.362, P < 0.002). Hepatic cholesterol content correlated positively with hepatic iron (R(2) = 0.255, P < 0.007). There was no significant relationship between plasma cholesterol and either hepatic cholesterol or iron (R(2) = 0.101 and 0.014, respectively). Hepatic iron did not correlate with a number of known regulators of cholesterol synthesis, including sterol-regulatory element binding factor 2 (Srebf2; R(2) = 0.015), suggesting that the increases seen in the cholesterol biosynthesis pathway are independent of Srebf2. Transcripts of genes involved in bile acid synthesis, transport, or regulation did not increase with increasing hepatic iron. CONCLUSION: This study suggests that hepatic iron loading increases liver cholesterol synthesis and provides a new and potentially important additional mechanism by which iron could contribute to the development of fatty liver disease or lipotoxicity.


Subject(s)
Cholesterol/biosynthesis , Iron/administration & dosage , Iron/physiology , Animals , Fatty Liver/etiology , Male , Mice , Mice, Inbred AKR
11.
World J Gastroenterol ; 16(6): 663-72, 2010 Feb 14.
Article in English | MEDLINE | ID: mdl-20135713

ABSTRACT

The carcinogenic potential of iron in colorectal cancer (CRC) is not fully understood. Iron is able to undergo reduction and oxidation, making it important in many physiological processes. This inherent redox property of iron, however, also renders it toxic when it is present in excess. Iron-mediated generation of reactive oxygen species via the Fenton reaction, if uncontrolled, may lead to cell damage as a result of lipid peroxidation and oxidative DNA and protein damage. This may promote carcinogenesis through increased genomic instability, chromosomal rearrangements as well as mutations of proto-oncogenes and tumour suppressor genes. Carcinogenesis is also affected by inflammation which is exacerbated by iron. Population studies indicate an association between high dietary iron intake and CRC risk. In this editorial, we examine the link between iron-induced oxidative stress and inflammation on the pathogenesis of CRC.


Subject(s)
Colorectal Neoplasms/etiology , Colorectal Neoplasms/physiopathology , Iron/physiology , Genomic Instability/physiology , Humans , Inflammation/physiopathology , Oxidative Stress/physiology
12.
J Hepatol ; 52(3): 425-31, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20133002

ABSTRACT

BACKGROUND & AIMS: Hereditary haemochromatosis type 3 is caused by mutations in transferrin receptor (TFR) 2. TFR2 has been shown to mediate iron transport in vitro and regulate iron homeostasis. The aim of this study was to determine the role of Tfr2 in iron transport in vivo using a Tfr2 mutant mouse. METHODS: Tfr2 mutant and wild-type mice were injected intravenously with (59)Fe-transferrin and tissue (59)Fe uptake was measured. Tfr1, Tfr2 and ferroportin expression was measured by real-time PCR and Western blot. Cellular localisation of ferroportin was determined by immunohistochemistry. RESULTS: Transferrin-bound iron uptake by the liver and spleen in Tfr2 mutant mice was reduced by 20% and 65%, respectively, whilst duodenal and renal uptake was unchanged compared with iron-loaded wild-type mice. In Tfr2 mutant mice, liver Tfr2 protein was absent, whilst ferroportin protein was increased in non-parenchymal cells and there was a low level of expression in hepatocytes. Tfr1 expression was unchanged compared with iron-loaded wild-type mice. Splenic Tfr2 protein expression was absent whilst Tfr1 and ferroportin protein expression was increased in Tfr2 mutant mice compared with iron-loaded wild-type mice. CONCLUSIONS: A small reduction in hepatic transferrin-bound iron uptake in Tfr2 mutant mice suggests that Tfr2 plays a minor role in liver iron transport and its primary role is to regulate iron metabolism. Increased ferroportin expression due to decreased hepcidin mRNA levels is likely to be responsible for impaired splenic iron uptake in Tfr2 mutant mice.


Subject(s)
Hemochromatosis/metabolism , Iron/metabolism , Receptors, Transferrin/metabolism , Transferrin/metabolism , Animals , Antimicrobial Cationic Peptides/metabolism , Biological Transport/physiology , Cation Transport Proteins/metabolism , Disease Models, Animal , Female , Hemochromatosis/genetics , Hepcidins , Liver/metabolism , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , RNA, Messenger/metabolism , Receptors, Transferrin/genetics , Spleen/metabolism
13.
Am J Physiol Cell Physiol ; 297(6): C1567-75, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19828835

ABSTRACT

Transferrin receptor (TFR) 1 and 2 are expressed in the liver; TFR1 levels are regulated by cellular iron levels while TFR2 levels are regulated by transferrin saturation. The aims of this study were to 1) determine the relative importance of TFR1 and TFR2 in transferrin-bound iron (TBI) uptake by HuH7 human hepatoma cells and 2) characterize the role of metal-transferrin complexes in the regulation of these receptors. TFR expression was altered by 1) incubation with metal-transferrin (Tf) complexes, 2) TFR1 and TFR2 small interfering RNA knockdown, and 3) transfection with a human TFR2 plasmid. TBI uptake was measured using (59)Fe-(125)I-labeled Tf and mRNA and protein expression by real-time PCR and Western blot analysis, respectively. Fe(2)Tf, Co(2)Tf, and Mn(2)Tf increased TFR2 protein expression, indicating that the upregulation was not specifically regulated by iron-transferrin but also other metal-transferrins. In addition, Co(2)Tf and Mn(2)Tf upregulated TFR1, reduced ferritin, and increased hypoxia-inducible factor-1alpha protein expression, suggesting that TFR1 upregulation was due to a combination of iron deficiency and chemical hypoxia. TBI uptake correlated with changes in TFR1 but not TFR2 expression. TFR1 knockdown reduced iron uptake by 80% while TFR2 knockdown did not affect uptake. At 5 microM transferrin, iron uptake was not affected by combined TFR1 and TFR2 knockdown. Transfection with a hTFR2 plasmid increased TFR2 protein expression, causing a 15-20% increase in iron uptake and ferritin levels. This shows for the first time that TFR-mediated TBI uptake is mediated primarily via TFR1 but not TFR2 and that a high-capacity TFR-independent pathway exists in hepatoma cells.


Subject(s)
Antigens, CD/metabolism , Carcinoma, Hepatocellular/metabolism , Iron/metabolism , Liver Neoplasms/metabolism , Receptors, Transferrin/metabolism , Transferrin/metabolism , Antigens, CD/genetics , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cobalt/metabolism , Humans , Iron/pharmacokinetics , Liver Neoplasms/pathology , Metals/metabolism , RNA, Small Interfering/pharmacology , Receptors, Transferrin/genetics , Transfection , Up-Regulation
14.
Crit Rev Clin Lab Sci ; 45(5): 451-84, 2008.
Article in English | MEDLINE | ID: mdl-18712630

ABSTRACT

Hereditary hemochromatosis (HH) comprises a group of inherited disorders of iron metabolism that can result in progressive iron overload, morbidity, and mortality, generally in adulthood. HFE-related HH is the most common type of HH and will form the core of this discussion. The discovery of new proteins and gene mutations has defined other types of HH, termed non-HFE HH. The regulatory protein hepcidin has a central role in iron homeostasis in these disorders. While the liver is the predominant organ of iron deposition and iron-overload-related disease in HFE-related HH, involvement of extrahepatic tissue can also result in morbidity and mortality if the disorder is not diagnosed before organ damage develops. This review traverses the road from HFE genotype to phenotype with a focus on clinical penetrance, modifier factors for disease expression, and current thoughts and controversies on HH diagnosis and screening.


Subject(s)
Hemochromatosis/physiopathology , Genotype , Hemochromatosis/diagnosis , Hemochromatosis/genetics , Homeostasis , Humans , Iron/metabolism , Phenotype
15.
Hepatology ; 47(5): 1737-44, 2008 May.
Article in English | MEDLINE | ID: mdl-18393371

ABSTRACT

UNLABELLED: HFE-related hereditary hemochromatosis results in hepatic iron overload. Hepatocytes acquire transferrin-bound iron via transferrin receptor (Tfr) 1 and Tfr1-independent pathways (possibly Tfr2-mediated). In this study, the role of Hfe in the regulation of hepatic transferrin-bound iron uptake by these pathways was investigated using Hfe knockout mice. Iron and transferrin uptake by hepatocytes from Hfe knockout, non-iron-loaded and iron-loaded wild-type mice were measured after incubation with 50 nM (125)I-Tf-(59)Fe (Tfr1 pathway) and 5 microM (125)I-Tf-(59)Fe (Tfr1-independent or putative Tfr2 pathway). Tfr1 and Tfr2 messenger RNA (mRNA) and protein expression were measured by real-time polymerase chain reaction and western blotting, respectively. Tfr1-mediated iron and transferrin uptake by Hfe knockout hepatocytes were increased by 40% to 70% compared with iron-loaded wild-type hepatocytes with similar iron levels and Tfr1 expression. Iron and transferrin uptake by the Tfr1-independent pathway was approximately 100-fold greater than by the Tfr1 pathway and was not affected by the absence of Hfe. Diferric transferrin increased hepatocyte Tfr2 protein expression, resulting in a small increase in transferrin but not iron uptake by the Tfr1-independent pathway. CONCLUSION: Tfr1-mediated iron uptake is regulated by Hfe in hepatocytes. The Tfr1-independent pathway exhibited a much greater capacity for iron uptake than the Tfr1 pathway but it was not regulated by Hfe. Diferric transferrin up-regulated hepatocyte Tfr2 protein expression but not iron uptake, suggesting that Tfr2 may have a limited role in the Tfr1-independent pathway.


Subject(s)
Hepatocytes/physiology , Histocompatibility Antigens Class I/physiology , Iron/metabolism , Membrane Proteins/physiology , Transferrin/metabolism , Animals , Biological Transport , Cell Culture Techniques , DNA Primers , Hemochromatosis Protein , Hepatocytes/cytology , Hepatocytes/metabolism , Histocompatibility Antigens Class I/genetics , Kinetics , Membrane Proteins/deficiency , Membrane Proteins/genetics , Mice , Mice, Knockout , Protein Binding , RNA/genetics , RNA/isolation & purification , RNA, Messenger/genetics
16.
J Hepatol ; 48(2): 327-34, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18083267

ABSTRACT

BACKGROUND/AIMS: Transferrin receptor 2 appears to have dual roles in iron metabolism; one is signalling, the other is iron transport. It is sensitive to high levels of diferric transferrin, which is associated with disorders of iron overload. Also present in these disorders are increased levels of plasma non-transferrin-bound iron. This study sought to clarify the role of transferrin receptor 2 in the uptake of transferrin-bound and non-transferrin-bound iron. METHODS: Variant Chinese Hamster Ovary (CHO) cells, transfected with transferrin receptor 2, were incubated with radio-labelled transferrin-bound or non-transferrin-bound iron. Competition studies were performed in the presence of unlabelled dimetallic transferrin; knockdown was performed using specific siRNA. RESULTS: Cells expressing transferrin receptor 2 bound and internalised transferrin and transferrin-bound iron. Transferrin recycling occurred with an average cycling time of 11-15 min. Interestingly, the presence of transferrin receptor 2 was also associated with uptake of non-transferrin-bound iron which was inhibited by unlabelled transferrin-bound metals. Knockdown reduced transferrin-bound and non-transferrin-bound iron uptake by approximately 60%. CONCLUSIONS: Transferrin receptor 2 mediates transferrin-bound iron uptake by receptor-mediated endocytosis. It is also involved in the uptake of non-transferrin-bound iron and the inhibition of non-transferrin-bound iron uptake by diferric transferrin in CHO cells.


Subject(s)
Iron/metabolism , Receptors, Transferrin/physiology , Transferrin/metabolism , Animals , CHO Cells , Cricetinae , Cricetulus , Humans , RNA, Small Interfering/pharmacology
17.
Crit Rev Clin Lab Sci ; 44(5-6): 413-59, 2007.
Article in English | MEDLINE | ID: mdl-17943492

ABSTRACT

While iron is an essential trace element required by nearly all living organisms, deficiencies or excesses can lead to pathological conditions such as iron deficiency anemia or hemochromatosis, respectively. A decade has passed since the discovery of the hemochromatosis gene, HFE, and our understanding of hereditary hemochromatosis (HH) and iron metabolism in health and a variety of diseases has progressed considerably. Although HFE-related hemochromatosis is the most widespread, other forms of HH have subsequently been identified. These forms are not attributed to mutations in the HFE gene but rather to mutations in genes involved in the transport, storage, and regulation of iron. This review is an overview of cellular iron metabolism and regulation, describing the function of key proteins involved in these processes, with particular emphasis on the liver's role in iron homeostasis, as it is the main target of iron deposition in pathological iron overload. Current knowledge on their roles in maintaining iron homeostasis and how their dysregulation leads to the pathogenesis of HH are discussed.


Subject(s)
Histocompatibility Antigens Class I/metabolism , Iron Metabolism Disorders/genetics , Iron-Binding Proteins/metabolism , Iron/metabolism , Liver/metabolism , Membrane Proteins/metabolism , Mutation , Anemia, Iron-Deficiency/metabolism , Animals , Antimicrobial Cationic Peptides/metabolism , Biological Transport , Cation Transport Proteins/metabolism , Ceruloplasmin/metabolism , GPI-Linked Proteins , Hemochromatosis/genetics , Hemochromatosis Protein , Hepcidins , Humans , Intestinal Absorption , Iron Overload/metabolism , Iron, Dietary/pharmacokinetics , Iron-Binding Proteins/genetics , Mutation/genetics , Receptors, Transferrin/deficiency , Receptors, Transferrin/genetics , Receptors, Transferrin/metabolism , Transferrin/deficiency , Transferrin/genetics , Transferrin/metabolism
18.
World J Gastroenterol ; 13(35): 4725-36, 2007 Sep 21.
Article in English | MEDLINE | ID: mdl-17729394

ABSTRACT

The liver plays a central role in iron metabolism. It is the major storage site for iron and also expresses a complex range of molecules which are involved in iron transport and regulation of iron homeostasis. An increasing number of genes associated with hepatic iron transport or regulation have been identified. These include transferrin receptors (TFR1 and 2), a ferrireductase (STEAP3), the transporters divalent metal transporter-1 (DMT1) and ferroportin (FPN) as well as the haemochromatosis protein, HFE and haemojuvelin (HJV), which are signalling molecules. Many of these genes also participate in iron regulatory pathways which focus on the hepatic peptide hepcidin. However, we are still only beginning to understand the complex interactions between liver iron transport and iron homeostasis. This review outlines our current knowledge of molecules of iron metabolism and their roles in iron transport and regulation of iron homeostasis.


Subject(s)
Iron/metabolism , Liver/metabolism , Biological Transport/genetics , Biological Transport/physiology , Homeostasis/genetics , Homeostasis/physiology , Humans , Kupffer Cells/metabolism , Liver/cytology
19.
J Hepatol ; 44(1): 176-82, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16271796

ABSTRACT

BACKGROUND/AIMS: In hereditary hemochromatosis, iron-loading of hepatocytes is associated with increased iron uptake while little is known about iron release. This study aims to characterise iron release and ferroportin expression by Hfe knockout hepatocytes to determine if they contribute to iron overload in haemochromatosis. METHODS: Iron release by hepatocytes from Hfe knockout, non-iron-loaded and iron-loaded wild-type mice was measured after incubation with nontransferrin-bound iron as iron-citrate. RESULTS: Iron release and ferroportin expression by hepatocytes from Hfe knockout, non-iron-loaded and in vivo iron-loaded wild-type mice were similar although, nontransferrin-bound iron uptake was significantly increased in Hfe knockout hepatocytes and decreased in iron-loaded wild-type hepatocytes compared with non-iron-loaded wild-type cells. When expressed as a percentage of total iron uptake, iron release was decreased in Hfe knockout hepatocytes (4.6+/-0.7 versus 13.7+/-1.2%, P<0.0001) and increased in iron-loaded wild-type hepatocytes (29.5+/-0.5 versus 13.5+/-0.7%; P<0.0001) compared with wild-type hepatocytes. In contrast, in vitro iron-loading increased iron release and ferroportin expression by both Hfe knockout and wild-type hepatocytes. CONCLUSIONS: Hfe knockout hepatocytes accumulate iron as a result of limited iron export and enhanced iron uptake. The correlation between iron release and ferroportin expression suggests that iron export in hepatocytes is mediated by ferroportin.


Subject(s)
Hemochromatosis/metabolism , Hepatocytes/metabolism , Iron/metabolism , Animals , Blotting, Western , Cation Transport Proteins/genetics , Cation Transport Proteins/metabolism , Cells, Cultured , Disease Models, Animal , Female , Gene Expression , Hemochromatosis/pathology , Hepatocytes/pathology , Male , Mice , Mice, Knockout , Polymerase Chain Reaction , RNA, Messenger/genetics
20.
Blood ; 104(5): 1519-25, 2004 Sep 01.
Article in English | MEDLINE | ID: mdl-15155457

ABSTRACT

Hereditary hemochromatosis (HH) is an iron-overload disorder caused by a C282Y mutation in the HFE gene. In HH, plasma nontransferrin-bound iron (NTBI) levels are increased and NTBI is bound mainly by citrate. The aim of this study was to examine the importance of NTBI in the pathogenesis of hepatic iron loading in Hfe knockout mice. Plasma NTBI levels were increased 2.5-fold in Hfe knockout mice compared with control mice. Total ferric citrate uptake by hepatocytes isolated from Hfe knockout mice (34.1 +/- 2.8 pmol Fe/mg protein/min) increased by 2-fold compared with control mice (17.8 +/- 2.7 pmol Fe/mg protein/min; P <.001; mean +/- SEM; n = 7). Ferrous ion chelators, bathophenanthroline disulfonate, and 2',2-bipyridine inhibited ferric citrate uptake by hepatocytes from both mouse types. Divalent metal ions inhibited ferric citrate uptake by hepatocytes, as did diferric transferrin. Divalent metal transporter 1 (DMT1) mRNA and protein expression was increased approximately 2-fold by hepatocytes from Hfe knockout mice. We conclude that NTBI uptake by hepatocytes from Hfe knockout mice contributed to hepatic iron loading. Ferric ion was reduced to ferrous ion and taken up by hepatocytes by a pathway shared with diferric transferrin. Inhibition of uptake by divalent metals and up-regulation of DMT1 expression suggested that NTBI uptake was mediated by DMT1.


Subject(s)
Ferric Compounds/pharmacokinetics , Hemochromatosis/genetics , Hemochromatosis/metabolism , Hepatocytes/metabolism , Iron/metabolism , Animals , Biological Transport/drug effects , Biological Transport/physiology , Cation Transport Proteins/genetics , Cation Transport Proteins/metabolism , Cobalt/pharmacology , Disease Models, Animal , Hydrogen-Ion Concentration , Iron Chelating Agents/pharmacology , Iron Radioisotopes , Iron-Binding Proteins/genetics , Iron-Binding Proteins/metabolism , Manganese/pharmacology , Mice , Mice, Inbred C57BL , Mice, Knockout , Phenanthrolines/pharmacology , RNA, Messenger/analysis , Transferrin/metabolism , Transferrin/pharmacology , Zinc/pharmacology
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