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Liver iron modulates hepcidin expression during chronically elevated erythropoiesis in mice

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dc.contributor.author Díaz, Víctor
dc.contributor.author Gammella, Elena
dc.contributor.author Recalcati, Stefania
dc.contributor.author Santambrogio, Paolo
dc.contributor.author Naldi, Arianne Monge
dc.contributor.author Vogel, Johannes
dc.contributor.author Gassmann, Max
dc.contributor.author Cairo, Gaetano
dc.date.accessioned 2022-01-04T20:29:59Z
dc.date.available 2022-01-04T20:29:59Z
dc.date.issued 2013
dc.identifier.uri https://hdl.handle.net/20.500.12866/10492
dc.description.abstract The liver-derived peptide hepcidin controls the balance between iron demand and iron supply. By inhibiting the iron export activity of ferroportin, hepcidin modulates iron absorption and delivery from the body's stores. The regulation of hepcidin, however, is not completely understood and includes a variety of different signals. We studied iron metabolism and hepcidin expression in mice constitutively overexpressing erythropoietin (Epo) (Tg6 mice), which leads to excessive erythropoiesis. We observed a very strong down-regulation of hepcidin in Tg6 mice that was accompanied by a strong increase in duodenal expression of ferroportin and divalent metal tranporter-1, as well as enhanced duodenal iron absorption. Despite these compensatory mechanisms, Tg6 mice displayed marked circulating iron deficiency and low levels of iron in liver, spleen, and muscle. To elucidate the primary signal affecting hepcidin expression during chronically elevated erythropoiesis, we increased iron availability by either providing iron (thus further increasing the hematocrit) or reducing erythropoiesis-dependent iron consumption by means of splenectomy. Both treatments increased liver iron and up-regulated hepcidin expression and the BMP6/SMAD pathway despite continuously high plasma Epo levels and sustained erythropoiesis. This suggests that hepcidin expression is not controlled by erythropoietic signals directly in this setting. Rather, these results indicate that iron consumption for erythropoiesis modulates liver iron content, and ultimately BMP6 and hepcidin. Analysis of the BMP6/SMAD pathway targets showed that inhibitor of DNA binding 1 (ID1) and SMAD7, but not transmembrane serine protease 6 (TMPRSS6), were up-regulated by increased iron availability and thus may be involved in setting the upper limit of hepcidin. Conclusion: We provide evidence that under conditions of excessive and effective erythropoiesis, liver iron regulates hepcidin expression through the BMP6/SMAD pathway. en_US
dc.language.iso eng
dc.publisher Wiley
dc.relation.ispartofseries Hepatology
dc.rights info:eu-repo/semantics/restrictedAccess
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/4.0/deed.es
dc.subject Animals en_US
dc.subject metabolism en_US
dc.subject nonhuman en_US
dc.subject controlled study en_US
dc.subject drug effects en_US
dc.subject priority journal en_US
dc.subject erythropoietin en_US
dc.subject animal experiment en_US
dc.subject animal model en_US
dc.subject Mice en_US
dc.subject mouse en_US
dc.subject physiology en_US
dc.subject iron en_US
dc.subject Iron en_US
dc.subject phenotype en_US
dc.subject down regulation en_US
dc.subject Down-Regulation en_US
dc.subject duodenum en_US
dc.subject Intestinal Absorption en_US
dc.subject intestine absorption en_US
dc.subject Up-Regulation en_US
dc.subject upregulation en_US
dc.subject article en_US
dc.subject liver en_US
dc.subject protein expression en_US
dc.subject biosynthesis en_US
dc.subject Bmp6 protein, mouse en_US
dc.subject bone morphogenetic protein 6 en_US
dc.subject Bone Morphogenetic Protein 6 en_US
dc.subject cation transport protein en_US
dc.subject Cation Transport Proteins en_US
dc.subject erythropoiesis en_US
dc.subject Erythropoiesis en_US
dc.subject ferroportin en_US
dc.subject hepcidin en_US
dc.subject Hepcidins en_US
dc.subject inhibitor of differentiation 1 en_US
dc.subject iron deficiency en_US
dc.subject iron storage en_US
dc.subject metal transporting protein 1 en_US
dc.subject Mice, Transgenic en_US
dc.subject Smad protein en_US
dc.subject Smad7 protein en_US
dc.subject Smad7 Protein en_US
dc.subject Smad7 protein, mouse en_US
dc.subject spleen en_US
dc.subject Spleen en_US
dc.subject transgenic mouse en_US
dc.title Liver iron modulates hepcidin expression during chronically elevated erythropoiesis in mice en_US
dc.type info:eu-repo/semantics/article
dc.identifier.doi https://doi.org/10.1002/hep.26550
dc.subject.ocde https://purl.org/pe-repo/ocde/ford#3.02.19
dc.relation.issn 1527-3350


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