title: Erythropoietin's inhibiting impact on hepcidin expression occurs indirectly.
abstract: Under conditions of accelerated erythropoiesis, elevated erythropoietin (Epo) levels are associated with inhibition of hepcidin synthesis, a response that ultimately increases iron availability to meet the enhanced iron needs of erythropoietic cells. In the search for erythroid regulators of hepcidin, many candidates have been proposed, including Epo itself. We aimed to test whether direct interaction between Epo and the liver is required to regulate hepcidin. We found that prolonged administration of high doses of Epo in mice leads to great inhibition of liver hepcidin mRNA levels, and concomitant induction of the hepcidin inhibitor erythroferrone (ERFE). Epo treatment also resulted in liver iron mobilization, mediated by increased ferroportin activity and accompanied by reduced ferritin levels and increased TfR1 expression. The same inhibitory effect was observed in mice that do not express the homodimeric Epo receptor (EpoR) in liver cells because EpoR expression is restricted to erythroid cells. Similarly, liver signaling pathways involved in hepcidin regulation were not influenced by the presence or absence of hepatic EpoR. Moreover, Epo analogs, possibly interacting with the postulated heterodimeric β common EpoR, did not affect hepcidin expression. These findings were supported by the lack of inhibition on hepcidin found in hepatoma cells exposed to various concentrations of Epo for different periods of times. Our results demonstrate that hepcidin suppression does not require the direct binding of Epo to its liver receptors and rather suggest that the role of Epo is to stimulate the synthesis of the erythroid regulator ERFE in erythroblasts, which ultimately downregulates hepcidin.
authors.affiliation: Department of Biomedical Sciences for Health, University of Milano, Milan, Italy;
authors.forename: Elena
authors.initials: E
authors.lastname: Gammella
authors.affiliation: Institute of Veterinary Physiology, Vetsuisse Faculty, and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland;
authors.forename: Victor
authors.initials: V
authors.lastname: Diaz
authors.affiliation: Department of Biomedical Sciences for Health, University of Milano, Milan, Italy;
authors.forename: Stefania
authors.initials: S
authors.lastname: Recalcati
authors.affiliation: Department of Biomedical Sciences for Health, University of Milano, Milan, Italy;
authors.forename: Paolo
authors.initials: P
authors.lastname: Buratti
authors.affiliation: Department of Health Science, University of Milano, Milan, Italy;
authors.forename: Michele
authors.initials: M
authors.lastname: Samaja
authors.affiliation: Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Soumyadeep
authors.initials: S
authors.lastname: Dey
authors.affiliation: Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Constance Tom
authors.initials: CT
authors.lastname: Noguchi
authors.affiliation: Institute of Veterinary Physiology, Vetsuisse Faculty, and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland; Universidad Peruana Cayetano Heredia, Lima, Peru.
authors.forename: Max
authors.initials: M
authors.lastname: Gassmann
authors.affiliation: Department of Biomedical Sciences for Health, University of Milano, Milan, Italy; gaetano.cairo@unimi.it.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Cairo
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000494:pharmacology; D056945:Hep G2 Cells; D064451:Hepcidins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000172:deficiency / Q000235:genetics; D013997:Time Factors
chemical_list: D016207:Cytokines; C572502:Erfe protein, mouse; D064451:Hepcidins; D009124:Muscle Proteins; D009842:Oligopeptides; D012333:RNA, Messenger; D017467:Receptors, Erythropoietin; C488171:carbamylated erythropoietin; D004921:Erythropoietin; C576178:cibinetide; D007501:Iron
keywords: bone morphogenetic protein 6; erythropoietin receptor; ferroportin; iron; liver