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Role of hepcidin in murine brain iron metabolism

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Abstract

Brain iron homeostasis is maintained by a balance of both iron uptake and release, and accumulating evidence has revealed that brain iron concentrations increase with aging. Hepcidin, an iron regulatory hormone produced by hepatocytes in response to inflammatory stimuli, iron, and hypoxia, has been shown to be the long-sought hormone responsible for the regulation of body iron balance and recycling in mammals. In this study, we report that hepcidin is widely expressed in the murine brain. In cerebral cortex, hippocampus and striatum, hepcidin mRNA levels increased with aging. Injection of hepcidin into the lateral cerebral ventricle resulted in decreased Fpn1 protein levels in cerebral cortex, hippocampus, and striatum. Additionally, treatment of primary cultured neurons with hepcidin caused decreased neuronal iron release and Fpn1 protein levels. Together, our data provide further evidence that hepcidin may be involved in the regulation of brain iron metabolism.

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References

  1. Chang YZ, Qian ZM, Wang K, Zhu L, Yang XD, Du JR, Jiang L, Ho KP, Wang Q, Ke Y (2005) Effects of development and iron status on ceruloplasmin expression in rat brain. J Cell Physiol 204:623–631

    Article  CAS  PubMed  Google Scholar 

  2. Ke Y, Chang YZ, Duan XL, Du JR, Zhu L, Wang K, Yang XD, Ho KP, Qian ZM (2005) Age-dependent and iron-independent expression of two mRNA isoforms of divalent metal transporter 1 in rat brain. Neurobiol Aging 26:739–748

    Article  CAS  PubMed  Google Scholar 

  3. Jellinger KA (1999) The role of iron in neurodegeneration: prospects for pharmacotherapy of Parkinson’s disease. Drugs Aging 14:115–140

    Article  CAS  PubMed  Google Scholar 

  4. Bishop GM, Robinson SR, Liu Q, Perry G, Atwood CS, Smith MA (2002) Iron: a pathological mediator of Alzheimer disease? Dev Neurosci 24:184–187

    Article  CAS  PubMed  Google Scholar 

  5. De Domenico I, Vaughn MB, Yoon D, Kushner JP, Ward DM, Kaplan J (2007) Zebrafish as a model for defining the functional impact of mammalian ferroportin mutations. Blood 110:3780–3783

    Article  PubMed  CAS  Google Scholar 

  6. Chang YZ, Ke Y, Du JR, Halpern GM, Ho KP, Zhu L, Gu XS, Xu YJ, Wang Q, Li LZ, Wang CY, Qian ZM (2006) Increased divalent metal transporter 1 expression might be associated with the neurotoxicity of l-DOPA. Mol Pharmacol 69:968–974

    CAS  PubMed  Google Scholar 

  7. Richardson DR (1999) Role of ceruloplasmin and ascorbate in cellular iron release. J Lab Clin Med 134:454–465

    Article  CAS  PubMed  Google Scholar 

  8. Chang YZ, Qian ZM, Du JR, Zhu L, Xu Y, Li LZ, Wang CY, Wang Q, Ge XH, Ho KP, Niu L, Ke Y (2007) Ceruloplasmin expression and its role in iron transport in C6 cells. Neurochem Int 50:726–733

    Article  CAS  PubMed  Google Scholar 

  9. Mukhopadhyay CK, Attieh ZK, Fox PL (1998) Role of ceruloplasmin in cellular iron uptake. Science 279:714–717

    Article  CAS  PubMed  Google Scholar 

  10. Qian ZM, Ke Y (2001) Rethinking the role of ceruloplasmin in brain iron metabolism. Brain Res Brain Res Rev 35:287–294

    Article  CAS  PubMed  Google Scholar 

  11. Xie JX, Tsoi YK, Chang YZ, Ke Y, Qian ZM (2002) Effects of ferroxidase activity and species on ceruloplasmin mediated iron uptake by BT325 cells. Brain Res Mol Brain Res 99:12–16

    Article  CAS  PubMed  Google Scholar 

  12. Chen Y, Qian ZM, Du J, Duan X, Chang Y, Wang Q, Wang C, Ma YM, Xu Y, Li L, Ke Y (2005) Iron loading inhibits ferroportin1 expression in PC12 cells. Neurochem Int 47:507–513

    Article  CAS  PubMed  Google Scholar 

  13. Aguirre P, Mena N, Tapia V, Arredondo M, Nunez MT (2005) Iron homeostasis in neuronal cells: a role for IREG1. BMC Neurosci 6:3

    Article  PubMed  CAS  Google Scholar 

  14. Park CH, Valore EV, Waring AJ, Ganz T (2001) Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 276:7806–7810

    Article  CAS  PubMed  Google Scholar 

  15. Viatte L, Lesbordes-Brion JC, Lou DQ, Bennoun M, Nicolas G, Kahn A, Canonne-Hergaux F, Vaulont S (2005) Deregulation of proteins involved in iron metabolism in hepcidin-deficient mice. Blood 105:4861–4864

    Article  CAS  PubMed  Google Scholar 

  16. Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot P, Loreal O (2001) A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem 276:7811–7819

    Article  CAS  PubMed  Google Scholar 

  17. Nicolas G, Chauvet C, Viatte L, Danan JL, Bigard X, Devaux I, Beaumont C, Kahn A, Vaulont S (2002) The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 110:1037–1044

    CAS  PubMed  Google Scholar 

  18. Nicolas G, Bennoun M, Devaux I, Beaumont C, Grandchamp B, Kahn A, Vaulont S (2001) Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci USA 98:8780–8785

    Article  CAS  PubMed  Google Scholar 

  19. Lou DQ, Nicolas G, Lesbordes JC, Viatte L, Grimber G, Szajnert MF, Kahn A, Vaulont S (2004) Functional differences between hepcidin 1 and 2 in transgenic mice. Blood 103:2816–2821

    Article  CAS  PubMed  Google Scholar 

  20. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J (2004) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306:2090–2093

    Article  CAS  PubMed  Google Scholar 

  21. Zechel S, Huber-Wittmer K, und Halbach O (2006) Distribution of the iron-regulating protein hepcidin in the murine central nervous system. J Neurosci Res 84:790–800

    Article  CAS  PubMed  Google Scholar 

  22. Clardy SL, Wang X, Boyer PJ, Earley CJ, Allen RP, Connor JR (2006) Is ferroportin–hepcidin signaling altered in restless legs syndrome? J Neurol Sci 247:173–179

    Article  CAS  PubMed  Google Scholar 

  23. Nicolas G, Bennoun M, Porteu A, Mativet S, Beaumont C, Grandchamp B, Sirito M, Sawadogo M, Kahn A, Vaulont S (2002) Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. Proc Natl Acad Sci USA 99:4596–4601

    Article  CAS  PubMed  Google Scholar 

  24. De Domenico I, Nemeth E, Nelson JM, Phillips JD, Ajioka RS, Kay MS, Kushner JP, Ganz T, Ward DM, Kaplan J (2008) The hepcidin-binding site on ferroportin is evolutionarily conserved. Cell Metab 8:146–156

    Article  PubMed  CAS  Google Scholar 

  25. Nemeth E, Preza GC, Jung CL, Kaplan J, Waring AJ, Ganz T (2006) The N-terminus of hepcidin is essential for its interaction with ferroportin: structure–function study. Blood 107:328–333

    Article  CAS  PubMed  Google Scholar 

  26. Peyssonnaux C, Zinkernagel AS, Datta V, Lauth X, Johnson RS, Nizet V (2006) TLR4-dependent hepcidin expression by myeloid cells in response to bacterial pathogens. Blood 107:3727–3732

    Article  CAS  PubMed  Google Scholar 

  27. Wang Q, Du F, Qian ZM, Ge XH, Zhu L, Yung WH, Yang L, Ke Y (2008) Lipopolysaccharide induces a significant increase in expression of iron regulatory hormone hepcidin in the cortex and substantia nigra in rat brain. Endocrinology 149:3920–3925

    Article  CAS  PubMed  Google Scholar 

  28. Dallalio G, Fleury T, Means RT (2003) Serum hepcidin in clinical specimens. Br J Haematol 122:996–1000

    Article  CAS  PubMed  Google Scholar 

  29. Masaki T, Yoshimatsu H, Chiba S, Watanabe T, Sakata T (2001) Central infusion of histamine reduces fat accumulation and upregulates UCP family in leptin-resistant obese mice. Diabetes 50:376–384

    Article  CAS  PubMed  Google Scholar 

  30. Rodriguez A, Pan P, Parkkila S (2007) Expression studies of neogenin and its ligand hemojuvelin in mouse tissues. J Histochem Cytochem 55:85–96

    Article  CAS  PubMed  Google Scholar 

  31. Theurl I, Ludwiczek S, Eller P, Seifert M, Artner E, Brunner P, Weiss G (2005) Pathways for the regulation of body iron homeostasis in response to experimental iron overload. J Hepatol 43:711–719

    Article  CAS  PubMed  Google Scholar 

  32. Kong WN, Zhao SE, Duan XL, Yang Z, Qian ZM, Chang YZ (2008) Decreased DMT1 and increased ferroportin 1 expression is the mechanisms of reduced iron retention in macrophages by erythropoietin in rats. J Cell Biochem 104:629–641

    Google Scholar 

  33. Kong WN, Chang YZ, Wang SM, Zhai XL, Shang JX, Li LX, Duan XL (2008) Effect of erythropoietin on hepcidin, DMT1 with IRE, and hephaestin gene expression in duodenum of rats. J Gastroenterol 43:136–143

    Article  CAS  PubMed  Google Scholar 

  34. Nagasawa K, Aoki H, Yasuda E, Nagai K, Shimohama S, Fujimoto S (2004) Possible involvement of group I mGluRs in neuroprotective effect of theanine. Biochem Biophys Res Commun 320:116–122

    Article  CAS  PubMed  Google Scholar 

  35. Kulaksiz H, Theilig F, Bachmann S, Gehrke SG, Rost D, Janetzko A, Cetin Y, Stremmel W (2005) The iron-regulatory peptide hormone hepcidin: expression and cellular localization in the mammalian kidney. J Endocrinol 184:361–370

    Article  CAS  PubMed  Google Scholar 

  36. Floyd RA, Carney JM (1993) The role of metal ions in oxidative processes and aging. Toxicol Ind Health 9:197–214

    CAS  PubMed  Google Scholar 

  37. Morris CM, Candy JM, Oakley AE, Bloxham CA, Edwardson JA (1992) Histochemical distribution of non-haem iron in the human brain. Acta Anat (Basel) 144:235–257

    Article  CAS  Google Scholar 

  38. Ke Y, Ming Qian Z (2003) Iron misregulation in the brain: a primary cause of neurodegenerative disorders. Lancet Neurol 2:246–253

    Article  CAS  PubMed  Google Scholar 

  39. Abboud S, Haile DJ (2000) A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem 275:19906–19912

    Article  CAS  PubMed  Google Scholar 

  40. Donovan A, Brownlie A, Zhou Y, Shepard J, Pratt SJ, Moynihan J, Paw BH, Drejer A, Barut B, Zapata A, Law TC, Brugnara C, Lux SE, Pinkus GS, Pinkus JL, Kingsley PD, Palis J, Fleming MD, Andrews NC, Zon LI (2000) Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 403:776–781

    Article  CAS  PubMed  Google Scholar 

  41. McKie AT, Marciani P, Rolfs A, Brennan K, Wehr K, Barrow D, Miret S, Bomford A, Peters TJ, Farzaneh F, Hediger MA, Hentze MW, Simpson RJ (2000) A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell 5:299–309

    Article  CAS  PubMed  Google Scholar 

  42. Jiang DH, Ke Y, Cheng YZ, Ho KP, Qian ZM (2002) Distribution of ferroportin1 protein in different regions of developing rat brain. Dev Neurosci 24:94–98

    Article  CAS  PubMed  Google Scholar 

  43. Wu LJ, Leenders AG, Cooperman S, Meyron-Holtz E, Smith S, Land W, Tsai RY, Berger UV, Sheng ZH, Rouault TA (2004) Expression of the iron transporter ferroportin in synaptic vesicles and the blood–brain barrier. Brain Res 1001:108–117

    Article  CAS  PubMed  Google Scholar 

  44. De Domenico I, Ward DM, di Patti MC, Jeong SY, David S, Musci G, Kaplan J (2007) Ferroxidase activity is required for the stability of cell surface ferroportin in cells expressing GPI-ceruloplasmin. EMBO J 26:2823–2831

    Article  PubMed  CAS  Google Scholar 

  45. Jeong SY, David S (2003) Glycosylphosphatidylinositol-anchored ceruloplasmin is required for iron efflux from cells in the central nervous system. J Biol Chem 278:27144–27148

    Article  CAS  PubMed  Google Scholar 

  46. Qian ZM, Shen X (2001) Brain iron transport and neurodegeneration. Trends Mol Med 7:103–108

    Article  CAS  PubMed  Google Scholar 

  47. Zecca L, Youdim MB, Riederer P, Connor JR, Crichton RR (2004) Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci 5:863–873

    Article  CAS  PubMed  Google Scholar 

  48. Roskams AJ, Connor JR (1994) Iron, transferrin, and ferritin in the rat brain during development and aging. J Neurochem 63:709–716

    Article  CAS  PubMed  Google Scholar 

  49. Pinero DJ, Li NQ, Connor JR, Beard JL (2000) Variations in dietary iron alter brain iron metabolism in developing rats. J Nutr 130:254–263

    CAS  PubMed  Google Scholar 

  50. Connor JR, Boyer PJ, Menzies SL, Dellinger B, Allen RP, Ondo WG, Earley CJ (2003) Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome. Neurology 61:304–309

    CAS  PubMed  Google Scholar 

  51. Allen RP, Barker PB, Wehrl F, Song HK, Earley CJ (2001) MRI measurement of brain iron in patients with restless legs syndrome. Neurology 56:263–265

    CAS  PubMed  Google Scholar 

  52. Liu XB, Yang F, Haile DJ (2005) Functional consequences of ferroportin 1 mutations. Blood Cells Mol Dis 35:33–46

    Article  CAS  PubMed  Google Scholar 

  53. Liu XB, Nguyen NB, Marquess KD, Yang F, Haile DJ (2005) Regulation of hepcidin and ferroportin expression by lipopolysaccharide in splenic macrophages. Blood Cells Mol Dis 35:47–56

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by National Natural Sciences Foundation of China (30570957, 30871260) and Natural Science Foundation of Hebei Province (C2007000251).

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Authors and Affiliations

  1. Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, 050016, Shijiazhuang, Hebei, People’s Republic of China

    S.-M. Wang, L.-J. Fu, X.-L. Duan, P. Yu, Z.-M. Qian, X.-J. Di, J. Li & Y.-Z. Chang

  2. Molecular Medicine Program, National Institute of Child Health and Human Development, Bethesda, MD, 20892, USA

    D. R. Crooks & T. A. Rouault

  3. Laboratory of Iron Metabolism, Department of Applied Biology and Chemical Technology, Hong Kong Polytechnic University, Jiulong, Hong Kong

    Z.-M. Qian

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  1. S.-M. Wang
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  2. L.-J. Fu
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Correspondence to Y.-Z. Chang.

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S.-M. Wang and L.-J. Fu contributed equally to this manuscript.

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Wang, SM., Fu, LJ., Duan, XL. et al. Role of hepcidin in murine brain iron metabolism. Cell. Mol. Life Sci. 67, 123–133 (2010). https://doi.org/10.1007/s00018-009-0167-3

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  • DOI: https://doi.org/10.1007/s00018-009-0167-3

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