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The Effectiveness of Different Doses of Iron Supplementation and the Prenatal Determinants of Maternal Iron Status in Pregnant Spanish Women: ECLIPSES Study. Nutrients 2019; 11:nu11102418. [PMID: 31658725 PMCID: PMC6835785 DOI: 10.3390/nu11102418] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 10/07/2019] [Accepted: 10/07/2019] [Indexed: 02/08/2023] Open
Abstract
Iron deficiency (ID), anemia, iron deficiency anemia (IDA) and excess iron (hemoconcentration) harm maternal–fetal health. We evaluated the effectiveness of different doses of iron supplementation adjusted for the initial levels of hemoglobin (Hb) on maternal iron status and described some associated prenatal determinants. The ECLIPSES study included 791 women, randomized into two groups: Stratum 1 (Hb = 110–130g/L, received 40 or 80mg iron daily) and Stratum 2 (Hb > 130g/L, received 20 or 40mg iron daily). Clinical, biochemical, and genetic information was collected during pregnancy, as were lifestyle and sociodemographic characteristics. In Stratum 1, using 80 mg/d instead of 40 mg/d protected against ID on week 36. Only women with ID on week 12 benefited from the protection against anemia and IDA by increasing Hb levels. In Stratum 2, using 20 mg/d instead of 40 mg/d reduced the risk of hemoconcentration in women with initial serum ferritin (SF) ≥ 15 μg/L, while 40 mg/d improved SF levels on week 36 in women with ID in early pregnancy. Mutations in the HFE gene increased the risk of hemoconcentration. Iron supplementation should be adjusted to early pregnancy levels of Hb and iron stores. Mutations of the HFE gene should be evaluated in women with high Hb levels in early pregnancy.
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Khan P, Shandilya A, Jayaram B, Islam A, Ahmad F, Hassan MI. Effect of pH on the stability of hemochromatosis factor E: a combined spectroscopic and molecular dynamics simulation-based study. J Biomol Struct Dyn 2016; 35:1582-1598. [PMID: 27174123 DOI: 10.1080/07391102.2016.1189359] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Hereditary hemochromatosis is an iron overburden condition, which is mainly governed by hereditary hemochromatosis factor E (HFE), a member of major histocompatibility complex class I. To understand the effect of pH on the structure and stability of HFE, we have cloned, expressed, and purified the HFE in the bacterial system and performed circular dichroism, fluorescence, and absorbance measurements at a wide pH range (pH 3.0-11.0). We found that HFE remains stable in the pH range 7.5-11.0 and gets completely acid denatured at low pH values. In this work, we also analyzed the contribution of salt bridges to the stability of HFE. We further performed molecular dynamics simulations for 80 ns at different pH values. An excellent agreement was observed between results from biophysical and MD simulation studies. At lower pH, HFE undergoes denaturation and may be driven toward a degradation pathway, such as ubiquitination. Hence, HFE is not available to bind again with transferrin receptor1 to negatively regulate iron homeostasis. Further we postulated that, might be low pH of cancerous cells helps them to meet their high iron requirement.
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Affiliation(s)
- Parvez Khan
- a Centre for Interdisciplinary Research in Basic Sciences , Jamia Millia Islamia , New Delhi 110025 , India
| | - Ashutosh Shandilya
- b Department of Chemistry , Indian Institute of Technology Delhi , New Delhi 110016 , India
| | - B Jayaram
- b Department of Chemistry , Indian Institute of Technology Delhi , New Delhi 110016 , India
| | - Asimul Islam
- a Centre for Interdisciplinary Research in Basic Sciences , Jamia Millia Islamia , New Delhi 110025 , India
| | - Faizan Ahmad
- a Centre for Interdisciplinary Research in Basic Sciences , Jamia Millia Islamia , New Delhi 110025 , India
| | - Md Imtaiyaz Hassan
- a Centre for Interdisciplinary Research in Basic Sciences , Jamia Millia Islamia , New Delhi 110025 , India
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3
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Samuel B, Fioravanti G, Polimera H, Mayer A, Dorville F, Little E. Autoimmune hepatitis in a 20-year-old African American man. Lab Med 2014; 45:161-71. [PMID: 24868999 DOI: 10.1309/lmag0di6ee4nycyn] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
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4
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Dostalikova-Cimburova M, Kratka K, Balusikova K, Chmelikova J, Hejda V, Hnanicek J, Neubauerova J, Vranova J, Kovar J, Horak J. Duodenal expression of iron transport molecules in patients with hereditary hemochromatosis or iron deficiency. J Cell Mol Med 2012; 16:1816-26. [PMID: 21973163 PMCID: PMC3822694 DOI: 10.1111/j.1582-4934.2011.01458.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Disturbances of iron metabolism are observed in chronic liver diseases. In the present study, we examined gene expression of duodenal iron transport molecules and hepcidin in patients with hereditary hemochromatosis (HHC) (treated and untreated), involving various genotypes (genotypes which represent risk for HHC were examined), and in patients with iron deficiency anaemia (IDA). Gene expressions of DMT1, ferroportin, Dcytb, hephaestin, HFE and TFR1 were measured in duodenal biopsies using real-time PCR and Western blot. Serum hepcidin levels were measured using ELISA. DMT1, ferroportin and TFR1 mRNA levels were significantly increased in post-phlebotomized hemochromatics relative to controls. mRNAs of all tested molecules were significantly increased in patients with IDA compared to controls. The protein expression of ferroportin was increased in both groups of patients but not significantly. Spearman rank correlations showed that DMT1 versus ferroportin, Dcytb versus hephaestin and DMT1 versus TFR1 mRNAs were positively correlated regardless of the underlying cause, similarly to protein levels of ferroportin versus Dcytb and ferroportin versus hephaestin. Serum ferritin was negatively correlated with DMT1 mRNA in investigated groups of patients, except for HHC group. A decrease of serum hepcidin was observed in IDA patients, but this was not statistically significant. Our data showed that although untreated HHC patients do not have increased mRNA levels of iron transport molecules when compared to normal subjects, the expression is relatively increased in relation to body iron stores. On the other hand, post-phlebotomized HHC patients had increased DMT1 and ferroportin mRNA levels possibly due to stimulated erythropoiesis after phlebotomy.
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Affiliation(s)
- Marketa Dostalikova-Cimburova
- Department of Cell and Molecular Biology & Center for Research of Diabetes, Metabolism and Nutrition, Third Faculty of Medicine, Charles University, Prague, Czech Republic
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5
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Transepithelial heme-iron transport: effect of heme oxygenase overexpression. Eur J Nutr 2010; 50:363-71. [DOI: 10.1007/s00394-010-0144-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2010] [Accepted: 11/02/2010] [Indexed: 12/31/2022]
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6
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Jayaranee S, Sthaneshwar P, Sokkalingam S. Serum prohepcidin concentrations in rheumatoid arthritis. Pathology 2009; 41:178-82. [DOI: 10.1080/00313020802436840] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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7
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Bhatt L, Horgan CP, McCaffrey MW. Knockdown of beta2-microglobulin perturbs the subcellular distribution of HFE and hepcidin. Biochem Biophys Res Commun 2008; 378:727-31. [PMID: 19059216 DOI: 10.1016/j.bbrc.2008.11.118] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2008] [Accepted: 11/19/2008] [Indexed: 12/14/2022]
Abstract
Hereditary Haemochromatosis is an iron overload disorder associated with mutations in the HFE gene, and to a lesser degree, the gene encoding its chaperone protein beta-2 microglobulin (beta2M). Here, we report that knockdown of beta2M by RNAi restricts HFE distribution to the endoplasmic reticulum (ER). Additionally, we demonstrate that hepcidin, an iron homeostasis-associated protein, localises predominantly to LBPA-positive late endosomes. Interestingly, we show that knockdown of beta2M by RNAi perturbs hepcidin localisation to late endosomes. In summary, our data suggest that beta2M is essential for the correct subcellular distribution of both HFE and hepcidin, two proteins, which are critical for iron homeostasis.
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Affiliation(s)
- Lavinia Bhatt
- Department of Biochemistry, Molecular Cell Biology Laboratory, Biosciences Institute, University College Cork, Cork, Ireland
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8
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Sebastiani G, Walker AP. HFE gene in primary and secondary hepatic iron overload. World J Gastroenterol 2007; 13:4673-89. [PMID: 17729389 PMCID: PMC4611189 DOI: 10.3748/wjg.v13.i35.4673] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2007] [Revised: 05/01/2007] [Accepted: 05/09/2007] [Indexed: 02/06/2023] Open
Abstract
Distinct from hereditary haemochromatosis, hepatic iron overload is a common finding in several chronic liver diseases. Many studies have investigated the prevalence, distribution and possible contributory role of excess hepatic iron in non-haemochromatotic chronic liver diseases. Indeed, some authors have proposed iron removal in liver diseases other than hereditary haemochromatosis. However, the pathogenesis of secondary iron overload remains unclear. The High Fe (HFE) gene has been implicated, but the reported data are controversial. In this article, we summarise current concepts regarding the cellular role of the HFE protein in iron homeostasis. We review the current status of the literature regarding the prevalence, hepatic distribution and possible therapeutic implications of iron overload in chronic hepatitis C, hepatitis B, alcoholic and non-alcoholic fatty liver diseases and porphyria cutanea tarda. We discuss the evidence regarding the role of HFE gene mutations in these liver diseases. Finally, we summarize the common and specific features of iron overload in liver diseases other than haemochromatosis.
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Affiliation(s)
- Giada Sebastiani
- Venetian Institute of Molecular Medicine (VIMM), Padova and Digestive Diseases, Hepatology and Clinical Nutrition Department, Umberto I Hospital, Venice, Italy.
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Hsiao PJ, Tsai KB, Shin SJ, Wang CL, Lee ST, Lee JF, Kuo KK. A novel mutation of transferrin receptor 2 in a Taiwanese woman with type 3 hemochromatosis. J Hepatol 2007; 47:303-6. [PMID: 17562347 DOI: 10.1016/j.jhep.2007.04.014] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2007] [Revised: 04/17/2007] [Accepted: 04/26/2007] [Indexed: 12/04/2022]
Abstract
Hereditary hemochromatosis (HH) is very rare in Asia. Here, we describe a Taiwanese woman presenting with fully developed characteristics of HH including bronze skin, DM, decreased MRI T2 signal intensity over liver and pituitary gland. Biochemistry of iron profile indicated a severe status of iron overload by serum iron: 194 microg/dL, serum ferritin: 6640 microg/L, transferrin saturation: 92.8%. By measuring the hepatic iron index 8.48 (>1.9) of her liver biopsy tissue, the diagnosis of HH was established. Diagnosis of non-HFE HH was carried out since the whole HFE genome was sequenced but failed to localize any genetic alterations. The whole genome of transferrin receptor 2 (TfR2) was sequenced and a novel mutation of 13528 G-->A (Arg 481 His) in exon 11 was detected. Therefore, type 3 hemochromatosis was confirmed. The distinct clinical features, extremely high iron index and impressive iron staining in her liver biopsy tissue may represent an aggravated iron deposition in the liver caused by this novel mutation. Our finding implicates functional importance of histidine in exchange of arginine at amino acid 481 of transferrin receptor 2 in iron homeostasis. This case reminds physicians in Asia to keep in mind that hemochromatosis could be a rare cause of DM.
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Affiliation(s)
- Pi-Jung Hsiao
- Division of Endocrinology and Metabolism, Department of Internal Medical, Kaohsiung Medical University, Taiwan, ROC
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10
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Malyszko J, Mysliwiec M. Hepcidin in Anemia and Inflammation in Chronic Kidney Disease. Kidney Blood Press Res 2007; 30:15-30. [PMID: 17215586 DOI: 10.1159/000098522] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Maintaining the correct iron balance is crucial for health. Our understanding of the molecular control of iron metabolism has increased dramatically over the past 5 years due to the discovery of hepcidin. This is a circulating antimicrobial peptide mainly synthesized in the liver, which has been recently proposed as a factor regulating the uptake of dietary iron and its mobilization from macrophages and hepatic stores. Inflammation causes an increase of production of hepcidin, which is a potent mediator of anemia of chronic diseases. Anemia in chronic kidney disease is mainly due to erythropoietin deficiency but these patients often have a chronic inflammatory state. The aim of this review is to summarize the current knowledge dealing with a possible role of hepcidin in iron metabolism and its regulation, particularly in kidney disease. In addition, current methods of determination of hepcidin are reviewed.
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Affiliation(s)
- Jolanta Malyszko
- Department of Nephrology and Transplantology, Medical University, Bialystok, Poland.
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11
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Tomosugi N, Kawabata H, Wakatabe R, Higuchi M, Yamaya H, Umehara H, Ishikawa I. Detection of serum hepcidin in renal failure and inflammation by using ProteinChip System. Blood 2006; 108:1381-7. [PMID: 16621968 DOI: 10.1182/blood-2005-10-4043] [Citation(s) in RCA: 207] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Hepcidin, a key regulator of iron metabolism, is expressed in the liver, distributed in blood, and excreted in urine. However, to date, no reliable and practical method for measuring the bioactive form of hepcidin in serum has been developed. Here, we used surface-enhanced laser desorption ionization time of flight mass spectrometry (SELDI-TOF MS) to analyze the distinctive serum proteomic patterns of patients receiving hemodialysis. In the range of 1000 to 15,000 m/z, we found 3 peptides at 2192, 2789, and 2851 m/z that showed a significant correlation with the serum ferritin levels. The molecular sizes of peptides at 2192 and 2789 m/z matched with the reported sizes of hepcidin-20 and -25, respectively, and the serum peptide at 2789 m/z was identified as hepcidin-25 by collision-induced dissociation tandem MS. By using SELDI-TOF MS, we developed a semiquantitative assay for hepcidin-25. In this assay, the level of serum hepcidin-25 correlated well with levels of serum ferritin and serum interleukin-6. Hepcidin-25 was found to accumulate in the serum of patients receiving hemodialysis; this could contribute to the pathogenesis of renal anemia by decreasing the available iron for hematopoiesis. Thus, SELDI-TOF MS would be a clinically useful tool to detect and semiquantify bioactive hepcidin in serum.
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Affiliation(s)
- Naohisa Tomosugi
- Division of Nephrology, Department of Internal Medicine, Kanazawa Medical University, Kahoku, Ishikawa 920-0293, Japan.
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Yokel RA, Lasley SM, Dorman DC. The speciation of metals in mammals influences their toxicokinetics and toxicodynamics and therefore human health risk assessment. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART B, CRITICAL REVIEWS 2006; 9:63-85. [PMID: 16393870 DOI: 10.1080/15287390500196230] [Citation(s) in RCA: 73] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/06/2023]
Abstract
Chemical form (i.e., species) can influence metal toxicokinetics and toxicodynamics and should be considered to improve human health risk assessment. Factors that influence metal speciation (and examples) include: (1) carrier-mediated processes for specific metal species (arsenic, chromium, lead and manganese), (2) valence state (arsenic, chromium, manganese and mercury), (3) particle size (lead and manganese), (4) the nature of metal binding ligands (aluminum, arsenic, chromium, lead, and manganese), (5) whether the metal is an organic versus inorganic species (arsenic, lead, and mercury), and (6) biotransformation of metal species (aluminum, arsenic, chromium, lead, manganese and mercury). The influence of speciation on metal toxicokinetics and toxicodynamics in mammals, and therefore the adverse effects of metals, is reviewed to illustrate how the physicochemical characteristics of metals and their handling in the body (toxicokinetics) can influence toxicity (toxicodynamics). Generalizing from mercury, arsenic, lead, aluminum, chromium, and manganese, it is clear that metal speciation influences mammalian toxicity. Methods used in aquatic toxicology to predict the interaction among metal speciation, uptake, and toxicity are evaluated. A classification system is presented to show that the chemical nature of the metal can predict metal ion toxicokinetics and toxicodynamics. Essential metals, such as iron, are considered. These metals produce low oral toxicity under most exposure conditions but become toxic when biological processes that utilize or transport them are overwhelmed, or bypassed. Risk assessments for essential and nonessential metals should consider toxicokinetic and toxicodynamic factors in setting exposure standards. Because speciation can influence a metal's fate and toxicity, different exposure standards should be established for different metal species. Many examples are provided which consider metal essentiality and toxicity and that illustrate how consideration of metal speciation can improve the risk assessment process. More examples are available at a website established as a repository for summaries of the literature on how the speciation of metals affects their toxicokinetics.
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Affiliation(s)
- Robert A Yokel
- Pharmaceutical Sciences, College of Pharmacy, and Graduate Center for Toxicology, University of Kentucky Medical Center, Lexington, KY 40536-0082, USA.
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Geier A, Gartung C, Theurl I, Weiss G, Lammert F, Dietrich CG, Weiskirchen R, Zoller H, Hermanns B, Matern S. Occult celiac disease prevents penetrance of hemochromatosis. World J Gastroenterol 2005; 11:3323-6. [PMID: 15929194 PMCID: PMC4316075 DOI: 10.3748/wjg.v11.i21.3323] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To report a patient with C282Y homozygocity, depleted body iron and intestinal atrophy caused by celiac disease (CD) who experienced resolution of the enteropathy with subsequent normalization of iron metabolism upon gluten-free diet.
METHODS: To obtain information on the tissue distribution and quantitative expression of proteins involved in duodenal iron trafficking, we determined the expression of divalent-metal transporter 1 (DMT1), ferroportin 1 (FP1) and transferrin receptor (TfR1) by means of immunohist-ochemistry and real-time PCR in duodenal biopsies of this patient.
RESULTS: Whereas in hereditary hemochromatosis patients without CD, DMT1 expression was up-regulated leading to excessive uptake of iron, we identified a significant reduction in protein and mRNA expression of DMT1 as a compensatory mechanism in this patient with HH and CD.
CONCLUSION: Occult CD may compensate for increased DMT1 expression in a specific subset of individuals with homozygous C282Y mutations in the hemochromatosis (HFE) gene, thus contributing to the low penetrance of HH.
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Affiliation(s)
- Andreas Geier
- Department of Internal Medicine III, Aachen University, Pauwelsstrasse 30, D-52074 Aachen, Germany.
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Crosbie J, Varma J, Mansfield J. Yersinia enterocolitica infection in a patient with hemachromatosis masquerading as proximal colon cancer with liver metastases: report of a case. Dis Colon Rectum 2005; 48:390-2. [PMID: 15812589 DOI: 10.1007/s10350-004-0777-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
A patient with genetic hemachromatosis presented with a clinical picture suggesting malignancy and CT evidence of lesions in the right colon and liver. Colonoscopy failed to confirm the suspected diagnosis. Blood and stool cultures were positive for yersinia enterocolittica infection. This case illustrates the need to confirm clinically and radiologically suspected malignancy. It also serves as a model of how localized gastrointestinal pathology can result from the interaction of host genetic factors and specific microbial species.
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Affiliation(s)
- James Crosbie
- Department of Gastroenterology and Colorectal Surgery, University of Newcastle upon Tyne, Royal Victoria Infirmary NE1 4LP, Newcastle upon Tyne, United Kingdom
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Abstract
Nutritional genomics has tremendous potential to change the future of dietary guidelines and personal recommendations. Nutrigenetics will provide the basis for personalized dietary recommendations based on the individual's genetic make up. This approach has been used for decades for certain monogenic diseases; however, the challenge is to implement a similar concept for common multifactorial disorders and to develop tools to detect genetic predisposition and to prevent common disorders decades before their manifestation. The preliminary results involving gene-diet interactions for cardiovascular diseases and cancer are promising, but mostly inconclusive. Success in this area will require the integration of different disciplines and investigators working on large population studies designed to adequately investigate gene-environment interactions. Despite the current difficulties, preliminary evidence strongly suggests that the concept should work and that we will be able to harness the information contained in our genomes to achieve successful aging using behavioral changes; nutrition will be the cornerstone of this endeavor.
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Affiliation(s)
- Jose M Ordovas
- Nutrition and Genomics Laboratory, Jean Mayer-U.S. Department of Agriculture, Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, USA.
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Loréal O, Le Lan C, Troadec MB, Guyader D, Brissot P. [Update on hemochromatosis]. GASTROENTEROLOGIE CLINIQUE ET BIOLOGIQUE 2004; 28:D92-102. [PMID: 15213669 DOI: 10.1016/s0399-8320(04)94993-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/30/2023]
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Brissot P, Troadec MB, Loréal O. Intestinal absorption of iron in HFE-1 hemochromatosis: local or systemic process? J Hepatol 2004; 40:702-9. [PMID: 15030990 DOI: 10.1016/j.jhep.2004.01.020] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Pierre Brissot
- Service des Maladies du Foie and Inserm Unit U-522, University Hospital Pontchaillou, Rennes, France.
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18
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Transcriptional regulation of intestinal nutrient transporters. MOLECULAR MECHANISMS CONTROLLING TRANSMEMBRANE TRANSPORT 2004. [DOI: 10.1007/b96814] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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Knutson M, Wessling-Resnick M. Iron metabolism in the reticuloendothelial system. Crit Rev Biochem Mol Biol 2003; 38:61-88. [PMID: 12641343 DOI: 10.1080/713609210] [Citation(s) in RCA: 221] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Comprised mainly of monocytes and tissue macrophages, the reticuloendothelial system (RES) plays two major roles in iron metabolism: it recycles iron from senescent red blood cells and it serves as a large storage depot for excess iron. Although iron recycling by the RES represents the largest pathway of iron efflux in the body, the precise mechanisms involved have remained elusive. However, studies characterizing the function and regulation of Nramp1, DMT1, HFE, FPN1, CD163, and hepcidin are rapidly expanding our knowledge of the molecular aspects of RE iron handling. This review summarizes fundamental physiological and biochemical aspects of iron metabolism in the RES and focuses on how recent studies have advanced our understanding of these areas. Also discussed are novel insights into the molecular mechanisms contributing to the abnormal RE iron metabolism characteristic of hereditary hemochromatosis and the anemia of chronic disease.
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Affiliation(s)
- Mitchell Knutson
- Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA.
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Abstract
Hemochromatosis is the clinical expression of iron overload and occurs as hereditary and secondary variants. In hereditary hemochromatosis, an inborn error in iron metabolism results in excess absorption of dietary iron, which gradually accumulates in the liver, pancreas, and heart. The most common form of hereditary hemochromatosis is related to homozygosity for the C282Y mutation in the HFE gene. Early diagnosis is essential because hereditary hemochromatosis is common, severe, and treatable. Early manifestations consist of asthenia, arthralgia, and serum transferrin saturation elevation. The C282Y mutation should be looked for to confirm the diagnosis in the patient and family members. Measurement of serum transferrin saturation followed by genetic testing in individuals with values above 45% is a reasonable screening strategy.
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Affiliation(s)
- Gérard Chalès
- Rheumatology department, Hôpital Sud, 16, boulevard de Bulgarie, BP 59129, 35065 Rennes, cedex 2, France.
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Gehrke SG, Kulaksiz H, Herrmann T, Riedel HD, Bents K, Veltkamp C, Stremmel W. Expression of hepcidin in hereditary hemochromatosis: evidence for a regulation in response to the serum transferrin saturation and to non-transferrin-bound iron. Blood 2003; 102:371-6. [PMID: 12637325 DOI: 10.1182/blood-2002-11-3610] [Citation(s) in RCA: 186] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Experimental data suggest the antimicrobial peptide hepcidin as a central regulator in iron homeostasis. In this study, we characterized the expression of human hepcidin in experimental and clinical iron overload conditions, including hereditary hemochromatosis. Using quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), we determined expression of hepcidin and the most relevant iron-related genes in liver biopsies from patients with hemochromatosis and iron-stain-negative control subjects. Regulation of hepcidin mRNA expression in response to transferrin-bound iron, non-transferrin-bound iron, and deferoxamine was analyzed in HepG2 cells. Hepcidin expression correlated significantly with serum ferritin levels in controls, whereas no significant up-regulation was observed in patients with hemochromatosis despite iron-overload conditions and high serum ferritin levels. However, patients with hemochromatosis showed an inverse correlation between hepcidin transcript levels and the serum transferrin saturation. Moreover, we found a significant correlation between hepatic transcript levels of hepcidin and transferrin receptor-2 irrespective of the iron status. In vitro data indicated that hepcidin expression is down-regulated in response to non-transferrin-bound iron. In conclusion, the presented data suggest a close relationship between the transferrin saturation and hepatic hepcidin expression in hereditary hemochromatosis. Although the causality is not yet clear, this interaction might result from a down-regulation of hepcidin expression in response to significant levels of non-transferrin-bound iron.
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Affiliation(s)
- Sven G Gehrke
- Department of Internal Medicine IV, University Hospital Heidelberg, Bergheimer Strasse 58, 69115 Heidelberg, Germany
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Pizarro F, Olivares M, Hertrampf E, Mazariegos DI, Arredondo M. Heme-iron absorption is saturable by heme-iron dose in women. J Nutr 2003; 133:2214-7. [PMID: 12840181 DOI: 10.1093/jn/133.7.2214] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
In developed countries where meat is an important constituent of the diet, much of the dietary iron is in the heme-iron form as hemoglobin and myoglobin. Heme-iron is absorbed more efficiently than inorganic iron by the human intestine. Thus, it is important to know how the dose of heme-iron affects iron absorption. The purpose of this study was to establish the dose-effect of heme-iron on the percentage and absolute amount of iron absorbed. Twenty-seven healthy women (28- to 50-y-old) were selected to participate in two iron absorption studies. Through the use of iron isotopes ((59)Fe and (55)Fe), the studies were performed to characterize the dose-response curve of non-heme-iron absorption (ferrous sulfate), and to establish the dose-response curve of heme-iron absorption (hemoglobin). The labeled hemoglobin was prepared by use of red blood cells from rabbits. The geometric means (+/-1 SEM range) of non-heme iron absorbed were 0.2 (0.2-0.3), 1.2 (1.0-1.5), 6.7 (5.7-8.0) and 13.0 (11.5-14.6) mg of iron for doses of 0.5, 5, 50 and 100 mg of iron as ferrous sulfate, respectively; and 0.1 (0.1-0.2), 0.4 (0.3-0.4), 2.2 (2.0-2.4) and 2.2 (1.7-3.0) mg of iron for doses of 0.5, 3, 15 and 30 mg of heme-iron as hemoglobin, respectively. The fitted curves for heme and non-heme iron differed (P < 0.04). These results strongly suggest that the heme-iron absorption pathway is saturable.
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Affiliation(s)
- Fernando Pizarro
- Institute of Nutrition and Food Technology (INTA) of University of Chile, Santiago, Chile.
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Abstract
Insights provided by molecular biology, immunohistochemistry, and transmission electron microscopy have increased our understanding of the pathogenesis and histopathology of hepatitis C virus (HCV) infection, nonalcoholic steatohepatitis (NASH), and bile ductular proliferative reactions in a number of liver diseases. Human and chimpanzee liver infected with HCV showed viral-like particles (50 to 60 nm in diameter) as well as aggregates of short tubules that represent viral envelope material. Interactions of HCV core protein with apolipoproteins have a role in the pathogenesis of HCV-related steatosis. Pathologists should be aware of the spectrum of liver pathology described with the use of highly active antiretroviral therapy (HAART) agents for the human immunodeficiency virus infection, which includes microvesicular steatosis and more severe hepatic injury with confluent necrosis. Proliferation of bile ductular structures is influenced by specific molecules and proteins (eg, the mucin-associated trefoil proteins and estrogens). The interplay between Notch receptors and Jagged 1 protein, as expressed by many cells of the liver (including bile duct epithelium) varies in primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC). Cholangiocarcinoma does not appear to be a long-term complication of small duct PSC. The fatty liver diseases, both alcoholic and nonalcoholic, are characterized by production of reactive oxygen species that have detrimental effects such as opening mitochondrial permeability transition pores with resultant release of cytochrome c into the cytosol. Hepatocellular carcinoma is now a recognized late complication of NASH. The derivation of hepatic stem cells, the roles of HFE protein and other hepatic and intestinal transport proteins in hemochromatosis, and the histopathologic interpretive challenge of centrilobular lesions in posttransplant liver biopsies are among other recent studies considered in this review.
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Affiliation(s)
- Jay H Lefkowitch
- College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA.
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Gehrke SG, Riedel HD, Herrmann T, Hadaschik B, Bents K, Veltkamp C, Stremmel W. UbcH5A, a member of human E2 ubiquitin-conjugating enzymes, is closely related to SFT, a stimulator of iron transport, and is up-regulated in hereditary hemochromatosis. Blood 2003; 101:3288-93. [PMID: 12480712 DOI: 10.1182/blood-2002-07-2192] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
SFT, a stimulator of iron (Fe) transport, has been described as a transmembrane protein that facilitates the uptake of ferrous and ferric iron in mammalian cells. This study was initiated to investigate the 5' regulatory region of SFT and its role in the etiology of hereditary hemochromatosis. Sequence analyses of the putative 5' regulatory region revealed that the SFT cDNA sequence corresponds to intron 6/exon 7 of UbcH5A, a member of E2 ubiquitin-conjugating enzymes, which is involved in the iron-dependent ubiquitination of the hypoxia-inducible factor (HIF) by the von Hippel-Lindau tumor suppressor (pVHL) E3 ligase complex. Further mRNA expression studies using a sequence-specific reverse transcriptase-polymerase chain reaction (RT-PCR) assay showed that UbcH5A is significantly up-regulated in the liver of iron-overloaded patients with hereditary hemochromatosis, as previously published for SFT. However, in vitro studies on HepG2 cells failed to demonstrate any significant UbcH5A regulation in response to iron loading or iron chelation. In conclusion, in vivo mRNA expression data previously obtained for SFT might be attributed to UbcH5A. The role of UbcH5A and the ubiquitination pathway in the etiology of hereditary hemochromatosis remains to be elucidated further.
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Affiliation(s)
- Sven G Gehrke
- Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany
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25
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Bilello JP, Cable EE, Isom HC. Expression of E-cadherin and other paracellular junction genes is decreased in iron-loaded hepatocytes. THE AMERICAN JOURNAL OF PATHOLOGY 2003; 162:1323-38. [PMID: 12651624 PMCID: PMC1851226 DOI: 10.1016/s0002-9440(10)63928-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Iron overload in the liver may occur in the clinical conditions hemochromatosis and transfusion-dependent thalassemia or by long-term consumption of large amounts of dietary iron. As iron concentrations increase in the liver, cirrhosis develops, and subsequently the normal architecture of the liver deteriorates. The underlying mechanisms whereby iron loading of hepatocytes leads to the pathology of the liver are not understood. Similarly, a direct relationship between the expression levels of paracellular junction genes and altered hepatocellular physiology has been reported; however, no relationship has been identified between iron loading and the expression of paracellular junction genes. Here, we report that the expression of numerous paracellular junction genes was decreased in iron-loaded hepatocytes, leading to increased cellular permeability, increased baculovirus-mediated gene transfer, and decreased gap junction communication. Iron loading of hepatocytes resulted in decreased E-cadherin promoter activity and subsequently decreased E-cadherin mRNA and protein expression. The data presented in this study describe a clear relationship between iron overload and decreased expression of paracellular junction genes in hepatic cells of rat and human origin.
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Affiliation(s)
- John P Bilello
- Department of Microbiology and Immunology, Milton S. Hershey Medical Center, The Penn State College of Medicine, Hershey, Pennsylvania 17033, USA
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26
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Moe OW, Vazquez M, Kielar M. Iron metabolism in end stage renal failure: rationale for re-evaluation of parenteral iron therapy. Curr Opin Nephrol Hypertens 2003; 12:145-51. [PMID: 12589174 DOI: 10.1097/00041552-200303000-00004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
PURPOSE OF REVIEW In this article we will examine the basis for using chronic high dose parenteral iron therapy in dialysis patients. RECENT FINDINGS There are increasing data that dialysis patients fare better in many respects if they have higher hematocrit values although the real optimal hematocrit has not been defined. There is an increasing tendency to use parenteral iron to achieve this goal. SUMMARY Although parenteral iron achieves seemingly favourable short results, there are no data for its safety in the long term. On the contrary, there are reasons to suggest possible iron overload with chronic use.
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Affiliation(s)
- Orson W Moe
- Department of Internal Medicine, University of Texas Southwestern Medical Center and Medical Service, Dallas 75390, USA.
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Guix P, Parera M, Castro JA, Picornell A, Ramón MM, Obrador A. [Molecular aspects of duodenal iron absorption]. GASTROENTEROLOGIA Y HEPATOLOGIA 2003; 26:86-93. [PMID: 12570892 DOI: 10.1016/s0210-5705(03)79047-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- P Guix
- Servicio de Análisis Clínicos. Hospital Universitario Son Dureta. Palma de Mallorca. Spain
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28
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Abstract
After identification of the hereditary haemochromatosis gene HFE, and receipt of confirmation that most patients with the condition were homozygous for a single, founder mutation (C282Y), most assumed that C282Y would be a prevalent, highly penetrant mutation in a gene that plays a key part in the regulation of iron absorption and of whole-body iron homoeostasis. With carrier rates of between 10% and 15%, and a homozygote frequency of about one-in-150 in people of northern European descent, C282Y is certainly prevalent. However, it is not highly penetrant. The pronounced variation in phenotype in individuals with the same gene mutation has prompted the search for modifier genes at other loci, and for environmental factors that might affect expression of the condition. Progress in our understanding of how HFE regulates the absorption of dietary iron has been slow, but much can be learnt from the study of the rare instances of haemochromatosis that involve mutations in newly-identified iron-metabolism genes, such as TFR2--a transferrin receptor isoform--and ferroportin1/Ireg1/mtp1--an intestinal iron transporter. The availability of definitive information on penetrance and the identity of genetic modifiers will aid the debate on whether population screening for haemochromatosis should be undertaken or whether alternative strategies should be implemented to improve early detection.
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Affiliation(s)
- Adrian Bomford
- Institute of Liver Studies, king'sCollege hospital, London, UK
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Schwake L, Henkel AW, Riedel HD, Stremmel W. Patch-clamp capacitance measurements: new insights into the endocytic uptake of transferrin. Blood Cells Mol Dis 2002; 29:459-64. [PMID: 12547236 DOI: 10.1006/bcmd.2002.0584] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Since its introduction by Neher and Sakmann in 1976 the patch-clamp technique has been extensively used to study processes such as signalling and synaptic transmission, but also for monitoring endo- and exocytosis. Since biological membranes behave like electrical capacitors high-resolution measurements of membrane capacitance allow detection of small changes in membrane surface area that accompany exocytosis and endocytosis. We here describe our recent work on patch-clamp capacitance measurements in stably transfected HeLa cells expressing HFE, the hereditary hemochromatosis gene product, under the control of a tetracycline-sensitive promotor. By means of whole-cell and cell-attached techniques we were able to reveal transferrin-induced decreases in membrane capacitance reflecting increased endocytosis at the single cell level. Moreover, cell-attached recordings revealed significant alterations in the formation of single endocytic vesicles. Time-resolved measurements of cell membrane capacitance provide a new methodological approach to study the endocytic uptake of transferrin and its regulation by HFE, the hereditary hemochromatosis protein.
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Affiliation(s)
- Lukas Schwake
- Department of Internal Medicine (Gastroenterology), Faculty of Medicine, University of Heidelberg, Bergheimer-Strasse 58, D-69115 Heidelberg, Germany.
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Zoller H, Theurl I, Koch R, Kaser A, Weiss G. Mechanisms of iron mediated regulation of the duodenal iron transporters divalent metal transporter 1 and ferroportin 1. Blood Cells Mol Dis 2002; 29:488-97. [PMID: 12547239 DOI: 10.1006/bcmd.2002.0587] [Citation(s) in RCA: 87] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Intestinal iron absorption is regulated by the body's demands for iron. Identification of divalent metal transporter 1 (DMT1) and ferroportin 1 (FPN1) has improved our understanding of iron transport across the intestinal epithelium. Although DMT1 and FPN1 mRNA bear an iron responsive element (IRE) within its untranslated regions which should cause susceptibility to iron mediated posttranscriptional regulation the latter has not been shown so far. The effects of iron perturbations on DMT1 and FPN1 expression were investigated in CaCo2 cells and in primary tissue cultures of human duodenal biopsies by means of Northern Blot, Western Blot, RNA-bandshift and Nuclear Run off analysis. Both DMT1 and FPN1 mRNA levels were increased upon treatment of CaCo2 cells with desferrioxamine, whereas iron treatment resulted in the opposite effect. These changes were paralleled by the respective alterations in DMT1 and FPN1 protein expression. Although desferrioxamine treatment increased the binding affinity of iron regulatory protein-1 to DMT1- and FPN1-IRE, the mRNA half life of DMT1 mRNA remained unchanged. Nuclear run-off analysis then demonstrated that the effects of iron and desferrioxamine on DMT1 and FPN1 mRNA expression are rather due to modulation of transcription of these genes. Our results demonstrate that iron unidirectionally regulates the expression of the two ferrous ion transporters DMT1 and FPN1 by affecting their transcription. This provides evidence for a negative feed-back loop between intracellular iron availability and transmembrane iron transport.
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Affiliation(s)
- Heinz Zoller
- Department of Medicine, University Hospital of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria
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