Synthetic hepcidin causes rapid dose-dependent hypoferremia and is concentrated in ferroportin-containing organs.
Hepcidin is the principal iron regulatory hormone and its overproduction contributes to anemia of inflammation (AI). In vitro, hepcidin binds to and induces the degradation of the exclusive iron exporter ferroportin. We explored the effects and distribution of synthetic hepcidin in the mouse. A single intraperitoneal injection of hepcidin caused a rapid fall of serum iron in a dose-dependent manner, with a 50-microg dose resulting in iron levels 80% lower than in control mice. The full effect was seen within only 1 hour, consistent with a blockade of iron export from tissue stores and from macrophages involved in iron recycling. Serum iron remained suppressed for more than 48 hours after injection. Using radiolabeled hepcidin, we demonstrated that the serum concentration of hepcidin at the 50-microg dose was 1.4 microM, consistent with the inhibitory concentration of 50% (IC50) of hepcidin measured in vitro. Radiolabeled hepcidin accumulated in the ferroportin-rich organs, liver, spleen, and proximal duodenum. Our study highlights the central role of the hepcidin-ferroportin interaction in iron homeostasis. The rapid and sustained action of a single dose of hepcidin makes it an appealing agent for the prevention of iron accumulation in hereditary hemochromatosis.
Rivera
Seth
S
UCLA Department of Medicine, 10833 Le Conte Ave, CHS 37-131, Los Angeles, CA 90095, USA. sethrivera@mednet.ucla.edu
Nemeth
Elizabeta
E
Gabayan
Victoria
V
Lopez
Miguel A
MA
Farshidi
Dina
D
Ganz
Tomas
T
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D027682:Cation Transport Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D064451:Hepcidins; D006706:Homeostasis; D006801:Humans; D007501:Iron / Q000097:blood*; D000090463:Iron Deficiencies; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D000098742:Ferroportin
D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; C578702:HAMP protein, human; C579599:Hamp protein, mouse; D064451:Hepcidins; D000098742:Ferroportin; D007501:Iron