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Hepcidin Treatment Modulates the Expression of Divalent Metal Transporter-1, Ceruloplasmin, and Ferroportin-1 in the Rat Cerebral Cortex and Hippocampus

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Abstract

Elevated iron levels are considered to play a role in the neurodegenerative mechanisms that underlie Alzheimer's and Parkinson's disease. The linkage between hepcidin (Hepc) and ferroportin-1 (FPN1), the divalent metal transporter 1 (DMT1), and ceruloplasmin (CP) in the brain is unknown. To discern the role of Hepc in regulating the expression of these proteins, we investigated FPN1, DMT1, and CP protein and mRNA expression in the brain after the intracerebroventricular injection of Hepc. Our results show that after Hepc injection, expression of FPN1 mRNA and FPN1 protein was inhibited in the cerebral cortex and hippocampus. Furthermore, we showed a clear change of DMT1 and CP protein and mRNA levels in the brain. The immunohistochemical analysis revealed an increase of DMT1 and a decrease of CP levels. Semi-quantitative analysis using PCR methods showed an increase of DMT1(+IRE) mRNA, and a decrease of DMT1(−IRE) mRNA and CP mRNA levels. Since alterations in iron levels in the brain are causally linked to degenerative conditions such as Alzheimer's disease, an improved understanding of the regulation of iron transport protein expression such as FPN1, DMT1, and CP could lead to novel strategies for treatments.

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References

  1. Nemeth E, Ganz T (2006) Regulation of iron metabolism by hepcidin. Annu Rev Nutr 26:323–342

    Article  PubMed  CAS  Google Scholar 

  2. Finkenstedt A, Wolf E, Höfner E, Gasser BI, Bösch S, Bakry R, Creus M, Kremser C, Schocke M, Theurl M, Moser P, Schranz M, Bonn G, Poewe W, Vogel W, Janecke AR, Zoller H (2010) Hepatic but not brain iron is rapidly chelated by deferasirox in aceruloplasminemia due to a novel gene mutation. J Hepatol 53:1101–1107

    Article  PubMed  CAS  Google Scholar 

  3. 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  Google Scholar 

  4. Donovan A, Lima CA, Pinkus JL, Pinkus GS, Zon LI, Robine S, Andrews NC (2005) The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab 1:191–200

    Article  PubMed  CAS  Google Scholar 

  5. Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot P, Loréal 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  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  7. 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  PubMed  CAS  Google Scholar 

  8. 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

    PubMed  CAS  Google Scholar 

  9. Chao HM, Chen YH, Liu JH, Lee SM, Lee FL, Chang Y, Yeh PH, Pan WH, Chi CW, Liu TY, Lui WY, Ho LT, Kuo CD, Lin DE, Chan CC, Yang DM, Lin AM, Chao FP (2008) Iron-generated hydroxyl radicals kill retinal cells in vivo: effect of ferulic acid. Hum Exp Toxicol 27:327–339

    Article  PubMed  CAS  Google Scholar 

  10. Barnham KJ, Bush AI (2008) Metals in Alzheimer's and Parkinson's diseases. Curr Opin Chem Biol 12:222–228

    Article  PubMed  CAS  Google Scholar 

  11. Song N, Jiang H, Wang J, Xie JX (2007) Divalent metal transporter 1 up-regulation is involved in the 6-hydroxydopamine-induced ferrous iron influx. J Neurosci Res 85:3118–3126

    Article  PubMed  CAS  Google Scholar 

  12. Knutson M, Menzies S, Connor J, Wessling-Resnick M (2004) Developmental, regional, and cellular expression of SFT/UbcH5A and DMT1 mRNA in brain. J Neurosci Res 76:633–641

    Article  PubMed  CAS  Google Scholar 

  13. Berg D, Hochstrasser H (2006) Iron metabolism in parkinsonian syndromes. Mov Disord 9:1299–1310

    Article  Google Scholar 

  14. Hellman NE, Gitlin JD (2002) Ceruloplasmin metabolism and function. Annu Rev Nutr 22:439–458

    Article  PubMed  CAS  Google Scholar 

  15. Mena NP, Esparza A, Tapia V, Valdés P, Núñez MT (2008) Hepcidin inhibits apical iron uptake in intestinal cells. Am J Physiol Gastrointest Liver Physiol 294:192–198

    Article  Google Scholar 

  16. Yamaji S, Sharp P, Ramesh B, Srai SK (2004) Inhibition of iron transport across human intestinal epithelial cells by hepcidin. Blood 104:2178–2180

    Article  PubMed  CAS  Google Scholar 

  17. Ge XH, Wang Q, Qian ZM, Zhu L, Du F, Yung WH, Yang L, Ke Y (2009) The iron regulatory hormone hepcidin reduces ferroportin 1 content and iron release in H9C2 cardiomyocytes. J Nutr Biochem 20:860–865

    Article  PubMed  CAS  Google Scholar 

  18. Chung B, Chaston T, Marks J, Srai SK, Sharp PA (2009) Hepcidin decreases iron transporter expression in vivo in mouse duodenum and spleen and in vitro in THP-1 macrophages and intestinal Caco-2 cells. J Nutr 139:1457–1462

    Article  PubMed  CAS  Google Scholar 

  19. Anderson GJ, Frazer DM, McKie AT, Vulpe CD, Smith A (2005) Mechanisms of haem and non-haem iron absorption: lessons from inherited disorders of iron metabolism. Biometals 18:339–348

    Article  PubMed  CAS  Google Scholar 

  20. Roth JA, Horbinski C, Feng L, Dolan KG, Higgins D, Garrick MD (2000) Differential localization of divalent metal transporter 1 with and without iron response element in rat PC12 and sympathetic neuronal cells. J Neurosci 20:7595–7601

    PubMed  CAS  Google Scholar 

  21. Chen L, Dentchev T, Wong R (2003) Increase expression of ceruloplasmin in the retina following photic injury. Mol Vis 9:151–158

    PubMed  CAS  Google Scholar 

  22. 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  PubMed  CAS  Google Scholar 

  23. Ganz T, Nemeth E (2006) Regulation of iron acquisition and iron distribution in mammals. Biochim Biophys Acta 1763:690–699

    Article  PubMed  CAS  Google Scholar 

  24. Mok H, Mlodnicka AE, Hentze MW, Muckenthaler M, Schumacher A (2006) The molecular circuitry regulating the switch between iron deficiency and overload in mice. J Biol Chem 281:7946–7951

    Article  PubMed  CAS  Google Scholar 

  25. Pietrangelo A (2006) Hereditary hemochromatosis. Biochim Biophys Acta 1763:700–710

    Article  PubMed  CAS  Google Scholar 

  26. Zecca L, Casella L, Albertini A, Bellei C, Zucca FA, Engelen M, Zadlo A, Szewczyk G, Zareba M, Sarna T (2008) Neuromelanin can protect against iron-mediated oxidative damage in system modeling iron overload of brain aging and Parkinson's disease. J Neurochem 106:1866–1875

    PubMed  CAS  Google Scholar 

  27. Hölscher C (2005) Development of beta-amyloid-induced neurodegeneration in Alzheimer's disease and novel neuroprotective strategies. Rev Neurosci 16:181–212

    Article  PubMed  Google Scholar 

  28. Wang SM, Fu LJ, Duan XL, Crooks DR, Yu P, Qian ZM, Di XJ, Li J, Rouault TA, Chang YZ (2010) Role of hepcidin in murine brain iron metabolism. Cell Mol Life Sci 67:123–133

    Article  PubMed  CAS  Google Scholar 

  29. Ke Y, Ho K, Du J, Zhu L, Xu Y, Wang Q, Wang CY, Li L, Ge X, Chang Y, Qian ZM (2006) Role of soluble ceruloplasmin in iron uptake by midbrain and hippocampus neurons. J Cell Biochem 98:912–919

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors wish to thank Dr. Zhong-Ming Qian in the Hong Kong Polytechnic University for his support. This work was supported by a Grant-in-Aid for Scientific Research (051015) from the ShanXi Science and Technology Department.

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Correspondence to Yue-Ze Liu.

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Li, L., Holscher, C., Chen, BB. et al. Hepcidin Treatment Modulates the Expression of Divalent Metal Transporter-1, Ceruloplasmin, and Ferroportin-1 in the Rat Cerebral Cortex and Hippocampus. Biol Trace Elem Res 143, 1581–1593 (2011). https://doi.org/10.1007/s12011-011-8967-3

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  • DOI: https://doi.org/10.1007/s12011-011-8967-3

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