title: Iron transferrin regulates hepcidin synthesis in primary hepatocyte culture through hemojuvelin and BMP2/4.
abstract: 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.
authors.affiliation: Departments of Pathology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1690, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Lin
authors.forename: Erika V
authors.initials: EV
authors.lastname: Valore
authors.forename: Elizabeta
authors.initials: E
authors.lastname: Nemeth
authors.forename: Julia B
authors.initials: JB
authors.lastname: Goodnough
authors.forename: Victoria
authors.initials: V
authors.lastname: Gabayan
authors.forename: Tomas
authors.initials: T
authors.lastname: Ganz
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis* / Q000235:genetics / Q000652:urine; D001059:Apoproteins / Q000378:metabolism; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D058851:GPI-Linked Proteins; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; D000071020:Hemochromatosis Protein; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D064451:Hepcidins; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014168:Transferrin / Q000378:metabolism / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D023181:Antimicrobial Cationic Peptides; D001059:Apoproteins; C525718:BMP2 protein, human; C525809:BMP4 protein, human; C525719:Bmp2 protein, mouse; C525810:Bmp4 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; C525887:GDF2 protein, human; D058851:GPI-Linked Proteins; C526108:Gdf2 protein, mouse; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; C578702:HAMP protein, human; C504414:HJV protein, mouse; C579599:Hamp protein, mouse; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D008565:Membrane Proteins; D012333:RNA, Messenger; D014168:Transferrin; D016212:Transforming Growth Factor beta; C028284:apotransferrin; C110714:holotransferrin