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Blood, 15 September 2007, Vol. 110, No. 6, pp. 2182-2189. Prepublished online as a Blood First Edition Paper on May 31, 2007; DOI 10.1182/blood-2007-04-087593. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-04-087593v1 110/6/2182    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Lin, L. Articles by Ganz, T. Search for Related Content PubMed PubMed Citation Articles by Lin, L. Articles by Ganz, T. Related Collections Red Cells Signal Transduction Gene Expression Free Research Articles Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  RED CELLS Iron transferrin regulates hepcidin synthesis in primary hepatocyte culture through hemojuvelin and BMP2/4 Lan Lin1, Erika V. Valore2, Elizabeta Nemeth2, Julia B. Goodnough1, Victoria Gabayan2, and Tomas Ganz1,2 Departments of1 Pathology and 2 Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA) The peptide hormone hepcidin is the principal regulator of systemic iron homeostasis. We examined the pathway by which iron stimulates the production of hepcidin. In humans who ingested 65 mg of iron, the increase in transferrin saturation preceded by hours the increase in urinary hepcidin excretion. Increases in urinary hepcidin concentrations were proportional to the increment in transferrin saturation. Paradoxically, in previous studies in primary hepatocytes and cell lines, hepcidin response to iron or iron transferrin was not observed. We now report that freshly isolated murine primary hepatocytes responded to holotransferrin but not apotransferrin by increasing hepcidin mRNA. Hepcidin increase was not due to contamination of the transferrin preparations by endotoxin, a potent pathologic stimulus of hepcidin synthesis. Using this culture system, we showed that holotransferrin concentrations regulate hepcidin mRNA concentrations through a hemojuvelin/BMP2/4–dependent pathway. Although BMP9 is known to be expressed in the liver and potently increased the basal concentrations of hepcidin mRNA, it did not interact with hemojuvelin, and interference with its signaling pathway did not affect iron regulation. Fresh primary hepatocytes constitute a sufficient system for the regulation of hepcidin by physiologic iron stimuli and will greatly facilitate studies of major disorders of iron homeostasis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Iron can boost hepcidin both ways Prem Ponka and Bill Andriopoulos Blood 2007 110: 1703-1704. [Full Text] [PDF] This article has been cited by other articles: L. Kautz, D. Meynard, A. Monnier, V. Darnaud, R. Bouvet, R.-H. Wang, C. Deng, S. Vaulont, J. Mosser, H. Coppin, et al. Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver Blood, August 15, 2008; 112(4): 1503 - 1509. [Abstract] [Full Text] [PDF] A.-S. Zhang, F. Yang, K. Meyer, C. Hernandez, T. Chapman-Arvedson, P. J. Bjorkman, and C. A. Enns Neogenin-mediated Hemojuvelin Shedding Occurs after Hemojuvelin Traffics to the Plasma Membrane J. Biol. Chem., June 20, 2008; 283(25): 17494 - 17502. [Abstract] [Full Text] [PDF] J. P. Pinto, S. Ribeiro, H. Pontes, S. Thowfeequ, D. Tosh, F. Carvalho, and G. Porto Erythropoietin mediates hepcidin expression in hepatocytes through EPOR signaling and regulation of C/EBP{alpha} Blood, June 15, 2008; 111(12): 5727 - 5733. [Abstract] [Full Text] [PDF] Y. Xia, J. L. Babitt, Y. Sidis, R. T. Chung, and H. Y. Lin Hemojuvelin regulates hepcidin expression via a selective subset of BMP ligands and receptors independently of neogenin Blood, May 15, 2008; 111(10): 5195 - 5204. [Abstract] [Full Text] [PDF] S. Liu, R. N.V.S. Suragani, A. Han, W. Zhao, N. C. Andrews, and J.-J. Chen Deficiency of heme-regulated eIF2{alpha} kinase decreases hepcidin expression and splenic iron in HFE-/- mice Haematologica, May 1, 2008; 93(5): 753 - 756. [Abstract] [Full Text] [PDF] R. Kuns-Hashimoto, D. Kuninger, M. Nili, and P. Rotwein Selective binding of RGMc/hemojuvelin, a key protein in systemic iron metabolism, to BMP-2 and neogenin Am J Physiol Cell Physiol, April 1, 2008; 294(4): C994 - C1003. [Abstract] [Full Text] [PDF] L. Silvestri, A. Pagani, and C. Camaschella Furin-mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis Blood, January 15, 2008; 111(2): 924 - 931. [Abstract] [Full Text] [PDF] A. Piperno, D. Girelli, E. Nemeth, P. Trombini, C. Bozzini, E. Poggiali, Y. Phung, T. Ganz, and C. Camaschella Blunted hepcidin response to oral iron challenge in HFE-related hemochromatosis Blood, December 1, 2007; 110(12): 4096 - 4100. [Abstract] [Full Text] [PDF]

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