Fetal liver hepcidin secures iron stores in utero

Kämmerer, Lara; Mohammad, Goran; Wolna, Magda; Robbins, Peter A.; Lakhal‐Littleton, Samira

doi:10.1182/blood.2019003907

Cited by 26 publications

(21 citation statements)

References 41 publications

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“…Molecular mechanisms controlling iron transporter protein expression in the placenta seem to involve the concerted action of the post‐transcriptional intracellular IRP/IRE system and post‐translational regulation by fetal hepcidin. The importance of IRPs (especially IRP1 47 ) in handling placental iron has been clearly demonstrated in human 47‐49 and animal 6,50 studies. Using an almost identical model of dietary iron deficiency in pregnant mouse females, Sanghke and co‐workers observed a 50% reduction in placental Fpn expression that was very likely mediated by IRP1 6 .…”

Section: Discussionmentioning

confidence: 99%

Marginally reduced maternal hepatic and splenic ferroportin under severe nutritional iron deficiency in pregnancy maintains systemic iron supply

et al. 2021

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The demand for iron is high in pregnancy to meet the increased requirements for erythropoiesis. Even pregnant females with initially iron‐replete stores develop iron‐deficiency anemia, due to inadequate iron absorption. In anemic females, the maternal iron supply is dedicated to maintaining iron metabolism in the fetus and placenta. Here, using a mouse model of iron deficiency in pregnancy, we show that iron recycled from senescent erythrocytes becomes a predominant source of this microelement that can be transferred to the placenta in females with depleted iron stores. Ferroportin is a key protein in the molecular machinery of cellular iron egress. We demonstrate that under iron deficiency in pregnancy, levels of ferroportin are greatly reduced in the duodenum, placenta and fetal liver, but not in maternal liver macrophages and in the spleen. Although low expression of both maternal and fetal hepcidin predicted ferroportin up‐regulation in examined locations, its final expression level was very likely correlated with tissue iron status. Our results argue that iron released into the circulation of anemic females is taken up by the placenta, as evidenced by high expression of iron importers on syncytiotrophoblasts. Then, a substantial decrease in levels of ferroportin on the basolateral side of syncytiotrophoblasts, may be responsible for the reduced transfer of iron to the fetus. As attested by the lowest decrease in iron content among analyzed tissues, some part is retained in the placenta. These findings confirm the key role played by ferroportin in tuning iron turnover in iron‐deficient pregnant mouse females and their fetuses.

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Section: Discussionmentioning

confidence: 99%

Marginally reduced maternal hepatic and splenic ferroportin under severe nutritional iron deficiency in pregnancy maintains systemic iron supply

et al. 2021

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“…Interestingly, in normal pregnancy, fetal hepcidin concentrations are very low in mice [ 50 ] and do not appear to contribute to baseline iron homeostasis or affect iron transport through placental ferroportin. However, fetal hepatic production of hepcidin may be sufficient to act on fetal hepatic ferroportin in an autocrine/paracrine manner to retain iron in the fetal liver [ 51 ] where it is used for fetal erythropoiesis until erythropoiesis transitions to the marrow, close to birth.…”

Section: Local Functions Of Ferroportin and Its Autocrine/paracrine Regulation By Hepcidinmentioning

confidence: 99%

Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis

Nemeth

Ganz

2021

IJMS

259

151

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Despite its abundance in the environment, iron is poorly bioavailable and subject to strict conservation and internal recycling by most organisms. In vertebrates, the stability of iron concentration in plasma and extracellular fluid, and the total body iron content are maintained by the interaction of the iron-regulatory peptide hormone hepcidin with its receptor and cellular iron exporter ferroportin (SLC40a1). Ferroportin exports iron from duodenal enterocytes that absorb dietary iron, from iron-recycling macrophages in the spleen and the liver, and from iron-storing hepatocytes. Hepcidin blocks iron export through ferroportin, causing hypoferremia. During iron deficiency or after hemorrhage, hepcidin decreases to allow iron delivery to plasma through ferroportin, thus promoting compensatory erythropoiesis. As a host defense mediator, hepcidin increases in response to infection and inflammation, blocking iron delivery through ferroportin to blood plasma, thus limiting iron availability to invading microbes. Genetic diseases that decrease hepcidin synthesis or disrupt hepcidin binding to ferroportin cause the iron overload disorder hereditary hemochromatosis. The opposite phenotype, iron restriction or iron deficiency, can result from genetic or inflammatory overproduction of hepcidin.

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“…During the postnatal period in rat liver a phase of hyperplasia is followed by hypertrophy and structural maturation to form mature hepatic sinusoids lined by a single layer of hepatocytes [23]. In addition to impacts of the Csf1rko on the IGF1 axis in the liver, transcriptional profiling indicated a broader delay in this postnatal hepatocyte maturation exemplified by the retention of fetal liver-expressed genes such as lipoprotein lipase ( Lpl )[57], fetal liver hepcidin ( Hamp ) [58] and the fetal amino acid transporter Slc38a2 [59]. Two other genes highly enriched in the liver of Csf1rko rats were the cold shock-inducible gene Rbm3 and stress-inducible Gadd45b.…”

Section: Discussionmentioning

confidence: 99%

CSF1R-dependent macrophages control postnatal somatic growth and organ maturation

Keshvari

Caruso

Batoon

et al. 2020

Preprint

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The development of the mononuclear phagocyte system (MPS) is controlled by signals from the CSF1 receptor (CSF1R). Homozygous mutation of the Csf1r locus (Csf1rko) in inbred rats led to the loss of non-classical monocytes and tissue macrophage populations, reduced postnatal somatic growth, severe developmental delay impacting all major organ systems and early mortality. The developmental impacts overlap with growth hormone/insulin-like growth factor (GH/IGF1) deficiency and Csf1rko rats lacked circulating IGF1. The liver is the main source of circulating IGF1. Expression profiling of juvenile wild-type and Csf1rko livers identified 2760 differentially expressed genes associated with the loss of macrophages, severe hypoplasia, delayed hepatocyte maturation, disrupted lipid metabolism and dysregulation of the GH/IGF1 system. Transfer of WT bone marrow at weaning restored circulating IGF1 and reversed the mutant phenotypes enabling long term survival and fertility. Phenotypic rescue was achieved without reconstituting blood monocytes or CSF1-responsive bone marrow progenitors. The results demonstrate that CSF1R-dependent macrophages control the growth and maturation of the liver and regulate the GH/IGF1 axis.

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Fetal liver hepcidin secures iron stores in utero

Cited by 26 publications

References 41 publications

Marginally reduced maternal hepatic and splenic ferroportin under severe nutritional iron deficiency in pregnancy maintains systemic iron supply

Marginally reduced maternal hepatic and splenic ferroportin under severe nutritional iron deficiency in pregnancy maintains systemic iron supply

Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis

CSF1R-dependent macrophages control postnatal somatic growth and organ maturation

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