Ferroportin and iron export from the macrophage

Summary

Principal Investigator: Mitchell D Knutson
Abstract: DESCRIPTION (provided by applicant): This application is for further training of the candidate, Mitchell Knutson, who has a Ph.D. in Nutrition and post-doctoral experience in the molecular biology of iron metabolism. Dr. Knutson's immediate career goal is to acquire new skills and knowledge that will enable him to study iron metabolism in macrophages. To accomplish this task, Dr. Knutson will be mentored by Dr. Lester Kobzik, an expert in macrophage biology at the Harvard School of Public Health (HSPH), and co-mentored by Dr. Marianne Wessling-Resnick, his current mentor at HSPH. The research proposal will investigate the function of the newly identified protein, ferroportin, FPN1 (also known as MTP1 or IREG1), in iron metabolism in the macrophage. The hypothesis to be tested is that FPN1 plays a role in iron export from the macrophage after phagocytosis of red blood cells. Erythrophagocytosis by macrophages, with the subsequent release of iron into the circulation, constitutes the largest flux of iron within the body. The mechanism for this, however, is unknown. To investigate the role of FPN1 in the macrophage, immunofluorescence experiments will determine the subcellular localization of this protein. Cytolocalization will be assessed before and after erythrophagocytosis. FPN1 mRNA and protein expression will be measured after erythrophagocytosis, and the changes will be compared to changes in rates of iron release, as measured by the efflux of 59Fe after phagocytosis of 59Fe-labeled erythrocytes. To test the hypothesis that FPN1 plays a role in iron release, efflux of erythrocyte-derived 59Fe will be measured after overexpressing FPN1 in macrophages using retroviral vector transduction, as well as after suppressing FPN1 using antisense techniques. The proximity of experts in macrophage biology, retroviral transduction, and antisense technology at HSPH, combined with the local expertise of investigators in the iron field, offers Dr. Knutson a highly suitable environment for learning the necessary skills required to carry out the proposed experiments. Successful completion of these experiments will contribute significantly to our understanding of iron metabolism in the macrophage and will enable Dr. Knutson to advance towards his long-term career goal of becoming an independent investigator and Assistant Professor of Nutrition. Moreover, a better understanding of iron release from the macrophage is of considerable clinical importance given the disturbances in macrophage iron metabolism characteristic of hereditary hemochromatosis and the anemia of chronic disease.
Funding Period: 2003-08-15 - 2008-07-31
more information: NIH RePORT

Top Publications

  1. pmc Iron release from macrophages after erythrophagocytosis is up-regulated by ferroportin 1 overexpression and down-regulated by hepcidin
    Mitchell D Knutson
    Food Science and Human Nutrition Department, University of Florida, Gainesville, FL 32611, USA
    Proc Natl Acad Sci U S A 102:1324-8. 2005
  2. pmc Zip14 (Slc39a14) mediates non-transferrin-bound iron uptake into cells
    Juan P Liuzzi
    Nutritional Genomics Laboratory, Food Science and Human Nutrition Department, Center for Nutritional Sciences, University of Florida, Gainesville, FL 32611 0370, USA
    Proc Natl Acad Sci U S A 103:13612-7. 2006
  3. ncbi Iron and iron-responsive proteins in the cardiomyopathy of Friedreich's ataxia
    Susan Michael
    Research Service, Veterans Affairs Medical Center, Albany, New York, USA
    Cerebellum 5:257-67. 2006
  4. ncbi The dentate nucleus in Friedreich's ataxia: the role of iron-responsive proteins
    Arnulf H Koeppen
    Research, Veterans Affairs Medical Center, Albany, NY 12208, USA
    Acta Neuropathol 114:163-73. 2007
  5. pmc The hereditary hemochromatosis protein, HFE, inhibits iron uptake via down-regulation of Zip14 in HepG2 cells
    Junwei Gao
    Department of Cell and Developmental Biology, Oregon Health and Science University, 3181 Sam Jackson Park Road, Portland, OR 97239, USA
    J Biol Chem 283:21462-8. 2008
  6. pmc Iron accumulation with age, oxidative stress and functional decline
    Jinze Xu
    Department of Aging and Geriatrics, Division of Biology of Aging, Genomics and Biomarkers Core of the Institute on Aging, University of Florida, Gainesville, Florida, United States of America
    PLoS ONE 3:e2865. 2008
  7. pmc Hepcidin regulation of iron transport
    James F Collins
    Department of Exercise and Nutrition Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214, USA
    J Nutr 138:2284-8. 2008
  8. pmc Iron loading increases ferroportin heterogeneous nuclear RNA and mRNA levels in murine J774 macrophages
    Fikret Aydemir
    Food Science and Human Nutrition Department, University of Florida, Gainesville, FL 32611, USA
    J Nutr 139:434-8. 2009

Scientific Experts

  • Mitchell D Knutson
  • Arnulf H Koeppen
  • Fikret Aydemir
  • James F Collins
  • Jinze Xu
  • Junwei Gao
  • Susan Michael
  • Juan P Liuzzi
  • Supak Jenkitkasemwong
  • Sukru Gulec
  • Marianne Wessling-Resnick
  • Christy S Carter
  • Ningning Zhao
  • Caroline A Enns
  • Christiaan Leeuwenburgh
  • Hyeyoung Nam
  • Michael D Garrick
  • Jiang Qian
  • Jacques B Lamarche
  • Simone V Petrocine
  • Robert J Cousins

Detail Information

Publications8

  1. pmc Iron release from macrophages after erythrophagocytosis is up-regulated by ferroportin 1 overexpression and down-regulated by hepcidin
    Mitchell D Knutson
    Food Science and Human Nutrition Department, University of Florida, Gainesville, FL 32611, USA
    Proc Natl Acad Sci U S A 102:1324-8. 2005
    ..We conclude that FPN1 is directly involved in the export of iron during erythrocyte-iron recycling by macrophages...
  2. pmc Zip14 (Slc39a14) mediates non-transferrin-bound iron uptake into cells
    Juan P Liuzzi
    Nutritional Genomics Laboratory, Food Science and Human Nutrition Department, Center for Nutritional Sciences, University of Florida, Gainesville, FL 32611 0370, USA
    Proc Natl Acad Sci U S A 103:13612-7. 2006
    ..Because NTBI is commonly found in plasma of patients with hemochromatosis and transfusional iron overload, Zip14-mediated NTBI uptake may contribute to the hepatic iron loading that characterizes these diseases...
  3. ncbi Iron and iron-responsive proteins in the cardiomyopathy of Friedreich's ataxia
    Susan Michael
    Research Service, Veterans Affairs Medical Center, Albany, New York, USA
    Cerebellum 5:257-67. 2006
    ..Progressive cardiomyopathy in FRDA is the likely result of iron-catalyzed mitochondrial damage followed by muscle fiber necrosis and a chronic reactive myocarditis...
  4. ncbi The dentate nucleus in Friedreich's ataxia: the role of iron-responsive proteins
    Arnulf H Koeppen
    Research, Veterans Affairs Medical Center, Albany, NY 12208, USA
    Acta Neuropathol 114:163-73. 2007
    ..Neuronal loss in the dentate nucleus is the likely result of trans-synaptic degeneration...
  5. pmc The hereditary hemochromatosis protein, HFE, inhibits iron uptake via down-regulation of Zip14 in HepG2 cells
    Junwei Gao
    Department of Cell and Developmental Biology, Oregon Health and Science University, 3181 Sam Jackson Park Road, Portland, OR 97239, USA
    J Biol Chem 283:21462-8. 2008
    ..Further analysis of protein turnover indicated that the half-life of Zip14 is lower in cells that express HFE. These results suggest that HFE decreases the stability of Zip14 and therefore reduces the iron loading in HepG2 cells...
  6. pmc Iron accumulation with age, oxidative stress and functional decline
    Jinze Xu
    Department of Aging and Geriatrics, Division of Biology of Aging, Genomics and Biomarkers Core of the Institute on Aging, University of Florida, Gainesville, Florida, United States of America
    PLoS ONE 3:e2865. 2008
    ..These findings strongly suggest that the age-related iron accumulation in muscle contributes to increased oxidative damage and sarcopenia, and that CR effectively attenuates these negative effects...
  7. pmc Hepcidin regulation of iron transport
    James F Collins
    Department of Exercise and Nutrition Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214, USA
    J Nutr 138:2284-8. 2008
    ..A particular focus is on molecular interactions between hepcidin and ferroportin, the regulation of hepcidin expression by iron and inflammation, and emerging methods to measure serum hepcidin in human populations...
  8. pmc Iron loading increases ferroportin heterogeneous nuclear RNA and mRNA levels in murine J774 macrophages
    Fikret Aydemir
    Food Science and Human Nutrition Department, University of Florida, Gainesville, FL 32611, USA
    J Nutr 139:434-8. 2009
    ..Collectively, these data are consistent with the hypothesis that iron increases macrophage ferroportin mRNA levels by inducing transcription of the ferroportin gene...