Liver iron modulates hepcidin expression during chronically elevated erythropoiesis in mice

Víctor Díaz, Elena Gammella, Stefania Recalcati, Paolo Santambrogio, Arianne Monge Naldi, Johannes Vogel, Max Gassmann, Gaetano Cairo

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2122-2132
Number of pages11
JournalHepatology
Volume58
Issue number6
DOIs
Publication statusPublished - Dec 2013

Fingerprint

Hepcidins
Erythropoiesis
Iron
Liver
Erythropoietin

ASJC Scopus subject areas

  • Hepatology
  • Medicine(all)

Cite this

Díaz, V., Gammella, E., Recalcati, S., Santambrogio, P., Naldi, A. M., Vogel, J., ... Cairo, G. (2013). Liver iron modulates hepcidin expression during chronically elevated erythropoiesis in mice. Hepatology, 58(6), 2122-2132. https://doi.org/10.1002/hep.26550

Liver iron modulates hepcidin expression during chronically elevated erythropoiesis in mice. / Díaz, Víctor; Gammella, Elena; Recalcati, Stefania; Santambrogio, Paolo; Naldi, Arianne Monge; Vogel, Johannes; Gassmann, Max; Cairo, Gaetano.

In: Hepatology, Vol. 58, No. 6, 12.2013, p. 2122-2132.

Research output: Contribution to journalArticle

Díaz, V, Gammella, E, Recalcati, S, Santambrogio, P, Naldi, AM, Vogel, J, Gassmann, M & Cairo, G 2013, 'Liver iron modulates hepcidin expression during chronically elevated erythropoiesis in mice', Hepatology, vol. 58, no. 6, pp. 2122-2132. https://doi.org/10.1002/hep.26550
Díaz, Víctor ; Gammella, Elena ; Recalcati, Stefania ; Santambrogio, Paolo ; Naldi, Arianne Monge ; Vogel, Johannes ; Gassmann, Max ; Cairo, Gaetano. / Liver iron modulates hepcidin expression during chronically elevated erythropoiesis in mice. In: Hepatology. 2013 ; Vol. 58, No. 6. pp. 2122-2132.
@article{12d572ff58db4fd39d83402f1213d3a1,
title = "Liver iron modulates hepcidin expression during chronically elevated erythropoiesis in mice",
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.",
author = "V{\'i}ctor D{\'i}az and Elena Gammella and Stefania Recalcati and Paolo Santambrogio and Naldi, {Arianne Monge} and Johannes Vogel and Max Gassmann and Gaetano Cairo",
year = "2013",
month = "12",
doi = "10.1002/hep.26550",
language = "English",
volume = "58",
pages = "2122--2132",
journal = "Hepatology",
issn = "0270-9139",
publisher = "John Wiley and Sons Inc.",
number = "6",

}

TY - JOUR

T1 - Liver iron modulates hepcidin expression during chronically elevated erythropoiesis in mice

AU - Díaz, Víctor

AU - Gammella, Elena

AU - Recalcati, Stefania

AU - Santambrogio, Paolo

AU - Naldi, Arianne Monge

AU - Vogel, Johannes

AU - Gassmann, Max

AU - Cairo, Gaetano

PY - 2013/12

Y1 - 2013/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84888291554&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84888291554&partnerID=8YFLogxK

U2 - 10.1002/hep.26550

DO - 10.1002/hep.26550

M3 - Article

VL - 58

SP - 2122

EP - 2132

JO - Hepatology

JF - Hepatology

SN - 0270-9139

IS - 6

ER -