title: Evidence for distinct pathways of hepcidin regulation by acute and chronic iron loading in mice.
abstract: In response to iron loading, hepcidin synthesis is homeostatically increased to limit further absorption of dietary iron and its release from stores. Mutations in HFE, transferrin receptor 2 (Tfr2), hemojuvelin (HJV), or bone morphogenetic protein 6 (BMP6) prevent appropriate hepcidin response to iron, allowing increased absorption of dietary iron, and eventually iron overload. To understand the role each of these proteins plays in hepcidin regulation by iron, we analyzed hepcidin messenger RNA (mRNA) responsiveness to short and long-term iron challenge in iron-depleted Hfe, Tfr2, Hjv, and Bmp6 mutant mice. After 1-day (acute) iron challenge, Hfe(-/-) mice showed a smaller hepcidin increase than their wild-type strain-matched controls, Bmp6(-/-) mice showed nearly no increase, and Tfr2 and Hjv mutant mice showed no increase in hepcidin expression, indicating that all four proteins participate in hepcidin regulation by acute iron changes. After a 21-day (chronic) iron challenge, Hfe and Tfr2 mutant mice increased hepcidin expression to nearly wild-type levels, but a blunted increase of hepcidin was seen in Bmp6(-/-) and Hjv(-/-) mice. BMP6, whose expression is also regulated by iron, may mediate hepcidin regulation by iron stores. None of the mutant strains (except Bmp6(-/-) mice) had impaired BMP6 mRNA response to chronic iron loading.
  
  
  CONCLUSIONS
  TfR2, HJV, BMP6, and, to a lesser extent, HFE are required for the hepcidin response to acute iron loading, but are partially redundant for hepcidin regulation during chronic iron loading and are not involved in the regulation of BMP6 expression. Our findings support a model in which acute increases in holotransferrin concentrations transmitted through HFE, TfR2, and HJV augment BMP receptor sensitivity to BMPs. A distinct regulatory mechanism that senses hepatic iron may modulate hepcidin response to chronic iron loading.
authors.affiliation: Chemistry and Biochemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: Emilio
authors.initials: E
authors.lastname: Ramos
authors.forename: Léon
authors.initials: L
authors.lastname: Kautz
authors.forename: Richard
authors.initials: R
authors.lastname: Rodriguez
authors.forename: Michael
authors.initials: M
authors.lastname: Hansen
authors.forename: Victoria
authors.initials: V
authors.lastname: Gabayan
authors.forename: Yelena
authors.initials: Y
authors.lastname: Ginzburg
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Roth
authors.forename: Elizabeta
authors.initials: E
authors.lastname: Nemeth
authors.forename: Tomas
authors.initials: T
authors.lastname: Ganz
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics*; D055418:Bone Morphogenetic Protein 6 / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006432:Hemochromatosis / Q000503:physiopathology; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D007501:Iron / Q000378:metabolism / Q000494:pharmacology*; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism; D011990:Receptors, Transferrin / Q000235:genetics; D014168:Transferrin / Q000494:pharmacology
chemical_list: D023181:Antimicrobial Cationic Peptides; C525817:Bmp6 protein, mouse; D055418:Bone Morphogenetic Protein 6; C579599:Hamp protein, mouse; D000071020:Hemochromatosis Protein; D064451:Hepcidins; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D012333:RNA, Messenger; D011990:Receptors, Transferrin; C503641:TFR2 protein, mouse; D014168:Transferrin; C110714:holotransferrin; D007501:Iron