title: Differences in activation of mouse hepcidin by dietary iron and parenterally administered iron dextran: compartmentalization is critical for iron sensing.
abstract: The iron regulatory hormone hepcidin responds to both oral and parenteral iron. Here, we hypothesized that the diverse iron trafficking routes may affect the dynamics and kinetics of the hepcidin activation pathway. To address this, C57BL/6 mice were administered an iron-enriched diet or injected i.p. with iron dextran and analyzed over time. After 1 week of dietary loading with carbonyl iron, mice exhibited significant increases in serum iron and transferrin saturation, as well as in hepatic iron, Smad1/5/8 phosphorylation and bone morphogenetic protein 6 (BMP6), and hepcidin mRNAs. Nevertheless, hepcidin expression reached a plateau afterward, possibly due to upregulation of inhibitory Smad7, Id1, and matriptase-2 mRNAs, while hepatic and splenic iron continued to accumulate over 9 weeks. One day following parenteral administration of iron dextran, mice manifested elevated serum and hepatic iron levels and Smad1/5/8 phosphorylation, but no increases in transferrin saturation or BMP6 mRNA. Surprisingly, hepcidin failed to appropriately respond to acute overload with iron dextran, and a delayed (after 5-7 days) hepcidin upregulation correlated with increased transferrin saturation, partial relocation of iron from macrophages to hepatocytes, and induction of BMP6 mRNA. Our data suggest that the physiological hepcidin response is saturable and are consistent with the idea that hepcidin senses exclusively iron compartmentalized within circulating transferrin and/or hepatocytes.
authors: Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, QC, Canada.
authors: Alina
authors: A
authors: Daba
authors: Konstantinos
authors: K
authors: Gkouvatsos
authors: Giada
authors: G
authors: Sebastiani
authors: Kostas
authors: K
authors: Pantopoulos
mesh_terms: D000284:Administration, Oral; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism*; D055418:Bone Morphogenetic Protein 6 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D064451:Hepcidins; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000378:metabolism; D007274:Injections, Intraperitoneal; D019266:Iron, Dietary / Q000008:administration & dosage / Q000378:metabolism*; D007505:Iron-Dextran Complex / Q000008:administration & dosage / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051897:Smad Proteins, Inhibitory / Q000235:genetics / Q000378:metabolism; D051896:Smad Proteins, Receptor-Regulated / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000378:metabolism*
chemical_list: D023181:Antimicrobial Cationic Peptides; C525817:Bmp6 protein, mouse; D055418:Bone Morphogenetic Protein 6; C579599:Hamp protein, mouse; D064451:Hepcidins; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D019266:Iron, Dietary; D008565:Membrane Proteins; D012333:RNA, Messenger; D051897:Smad Proteins, Inhibitory; D051896:Smad Proteins, Receptor-Regulated; D007505:Iron-Dextran Complex; D012697:Serine Endopeptidases; C467801:matriptase 2