Low hepcidin accounts for the proinflammatory status associated with iron deficiency

AbstractHepcidin is an antimicrobial peptide that controls systemic iron homeostasis. Hepcidin binding to its receptor ferroportin reduces iron availability, thus controlling microbial growth. In parallel it triggers an anti-inflammatory response in macrophages. Hepcidin is transcriptionally regulated by iron, through the bone morphogenetic protein–son of mothers against decapentaplegic (BMP-SMAD) pathway and by inflammation, through IL6-mediated STAT3 signaling. To investigate the mechanisms linking iron and inflammation, we treated C57BL/6 iron-deficient mice with a sublethal dose of lipopolysaccharide (LPS) and analyzed their inflammatory response in comparison with controls. We show that iron-deprived mice have a proinflammatory condition, exacerbated by LPS treatment leading to increased IL6 and TNFα mRNA in liver and spleen macrophages, and increased serum IL6 (482.29 ± 205.59 pg/mL) versus controls (69.01 ± 17.52 pg/mL; P < .05). Hepcidin was undetectable in iron-deficient mice but pretreatment with hepcidin normalized their response to LPS. Tmprss6−/− mice, characterized by iron deficiency and high hepcidin, show a blunted inflammatory response when challenged with LPS. Our data support a model in which the lack of hepcidin is responsible of the high inflammatory response to LPS in iron deficiency. The proinflammatory status associated with chronic iron deficiency could explain the resistance to infection seen in this condition.

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Maternal iron deficiency alters trophoblast differentiation and placental development in rat pregnancy

Endocrinology ◽

10.1210/endocr/bqab215 ◽

2021 ◽

Author(s):

Hannah Roberts ◽

Andrew G Woodman ◽

Kelly J Baines ◽

Mariyan J Jeyarajah ◽

Stephane L Bourque ◽

...

Keyword(s):

Iron Deficiency ◽

Fetal Growth ◽

Growth And Development ◽

Iron Homeostasis ◽

Junctional Zone ◽

Altered Expression ◽

Expression Of Genes ◽

Iron Deficient ◽

Increased Risk ◽

Maternal Iron

Abstract Iron deficiency occurs when iron demands chronically exceed intake, and is prevalent in pregnant women. Iron deficiency during pregnancy poses major risks for the baby, including fetal growth restriction and long-term health complications. The placenta serves as the interface between a pregnant mother and her baby, and ensures adequate nutrient provisions for the fetus. Thus, maternal iron deficiency may impact fetal growth and development by altering placental function. We used a rat model of diet-induced iron deficiency to investigate changes in placental growth and development. Pregnant Sprague-Dawley rats were fed either a low-iron or iron-replete diet starting two weeks before mating. Compared to controls, both maternal and fetal hemoglobin were reduced in dams fed low-iron diets. Iron deficiency decreased fetal liver and body weight, but not brain, heart or kidney weight. Placental weight was increased in iron deficiency, due primarily to expansion of the placental junctional zone. The stimulatory effect of iron deficiency on junctional zone development was recapitulated in vitro, as exposure of rat trophoblast stem cells to the iron chelator deferoxamine increased differentiation toward junctional zone trophoblast subtypes. Gene expression analysis revealed 464 transcripts changed at least 1.5-fold (P<0.05) in placentas from iron-deficient dams, including altered expression of genes associated with oxygen transport and lipoprotein metabolism. Expression of genes associated with iron homeostasis was unchanged despite differences in levels of their encoded proteins. Our findings reveal robust changes in placentation during maternal iron deficiency, which could contribute to the increased risk of fetal distress in these pregnancies.

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Effects of Iron Status and Iron Supplementation on Salmonella Typhimurium and Plasmodium Yoelii Infection In Mice

Blood ◽

10.1182/blood.v116.21.2052.2052 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2052-2052

Author(s):

Eldad A. Hod ◽

Eric H. Ekland ◽

Shruti Sharma ◽

Boguslaw S. Wojczyk ◽

David A. Fidock ◽

...

Keyword(s):

Iron Deficiency ◽

Salmonella Typhimurium ◽

Median Survival ◽

Iron Supplementation ◽

Iron Status ◽

Plasmodium Yoelii ◽

Oral Iron ◽

Deficiency Anemia ◽

Iron Deficient ◽

Deficient Mice

Abstract Abstract 2052 To clarify the interactions between iron status, oral iron supplementation, and bacterial and malarial infections, we examined iron-replete mice and mice with dietary iron deficiency infected with Salmonella typhimurium, Plasmodium yoelii, or both, with and without oral iron administration. These studies were designed to identify potential mechanisms underlying the increased risk of severe illness and death in children in a malaria-endemic region who received routine iron and folic acid supplementation during a randomized, controlled trial in Pemba, Tanzania (Sazawal et al. Lancet 2006;367:133-43). To this end, weanling C57BL/6 female mice were fed an iron-replete or an iron-deficient diet, the latter of which resulted in severe iron deficiency anemia. Groups of mice were then infected by intraperitoneal injection of Salmonella typhimurium strain LT2, Plasmodium yoelii strain 17X parasites, or both. With Salmonella infection alone, iron-deficient mice had a median survival (7.5 days, N=8) approximately half that of iron-replete mice (13 days, N=10, p<0.0001). At death, the mean level of bacteremia was significantly higher in infected iron-deficient mice. In blood cultures performed at death, all iron-deficient mice were bacteremic, but bacteria were detected in only 4 of 10 iron-replete mice. Both iron-deficient and iron-replete Salmonella-infected mice had gross hepatosplenomegaly with hepatitis, distorted hepatic and splenic architecture, massive expansion of the splenic red pulp with inflammatory cells, and Gram-negative bacilli by tissue Gram stain. With P. yoelii infection alone, iron-deficient and iron-replete mice cleared the infection at similar rates (by ~13 days following infection, N=5 in each group) and no deaths due to parasitemia occurred. With Salmonella and P. yoelii co-infection, death was earlier than with Salmonella alone in iron-replete mice (median survival of 10 vs. 13 days; N=10 in each group; p=0.005), but not in iron-deficient mice (median survival of 7 vs. 7.5 days; N=10 and 8, respectively; p=0.8). To examine the effect of short-term oral iron supplementation with Salmonella infection alone, mice received daily iron (ferrous sulfate, 1 mg/kg) by gavage for 4 days before infection with Salmonella, and supplementation continued for a total of 10 days. After gavage, plasma non-transferrin-bound iron (NTBI) appeared at 1–2 hours with a mean peak level of approximately 5 μM. In iron-deficient mice, short-term oral iron supplementation did not fully correct the iron deficiency anemia or replenish iron stores. Oral iron supplementation reduced the median survival of both iron-deficient and iron-replete Salmonella-infected mice by approximately 1 day; the difference was significant only in the iron-replete group (N=5, p<0.05). In summary, these results indicate that iron deficiency decreases the survival of Salmonella-infected mice; the median survival of iron-deficient mice was approximately half that of those that were iron replete. These observations are similar to those in the Pemba sub-study in which iron-deficient children given placebo had a 200% increase in the risk of adverse events relative to iron-replete children. Iron deficiency had no apparent effect on the course of infection with P. yoelii but further studies with more virulent Plasmodium species are needed. Co-infection with Salmonella and Plasmodium significantly increased mortality as compared to single infections, but only in iron-replete mice. Oral iron supplementation of Salmonella-infected mice significantly decreased the median survival, but only of iron-replete animals; however, our study may have had insufficient power to detect an effect on iron-deficient mice. Systematic examination in mice of the effect of iron supplements on the severity of malarial and bacterial infection in iron-replete and iron-deficient states may ultimately help guide the safe and effective use of iron interventions in humans in areas with endemic malaria. Disclosures: No relevant conflicts of interest to declare.

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Erythroferrone Modulates Iron Distribution for Fetal Erythropoiesis

Blood ◽

10.1182/blood-2021-153902 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 757-757

Author(s):

Veena Sangkhae ◽

Vivian Yu ◽

Richard Coffey ◽

Tomas Ganz ◽

Elizabeta Nemeth

Keyword(s):

Iron Deficiency ◽

Iron Homeostasis ◽

Minor Role ◽

Iron Availability ◽

Liver Iron ◽

Iron Deficient ◽

Embryo Liver ◽

A Minor ◽

Maternal Iron ◽

Iron Concentrations

Abstract Erythroferrone (ERFE) is an erythroblast-derived regulator of iron metabolism, and its production increases during stress erythropoiesis. ERFE decreases expression of the iron-regulatory hormone hepcidin to enhance iron availability for erythropoiesis 1. Pregnancy requires a substantial increase in iron availability to sustain a dramatic increase in maternal RBC volume and support fetal development. Whether maternal or fetal ERFE plays a role in regulating iron homeostasis during pregnancy is unknown. In humans, maternal ERFE concentrations were elevated in anemic pregnancies at mid gestation and delivery 2. To define the role of ERFE during iron-replete or iron-deficient pregnancy, we utilized Erfe transgenic (ETg) 3 and Erfe knockout (EKO) 1 mice. Maternal iron status of ETg, WT and EKO mice was altered by placing animals on adequate iron (100ppm) or low iron (4ppm) diet 2 weeks prior to and throughout pregnancy. ETg and WT dams were mated with WT sires to generate ETg and WT embryos while EKO dams were mated with EKO sires to generate EKO embryos. Analysis was performed at embryonic day 18.5. To examine the effect of pregnancy on ERFE expression, we compared non-pregnant females to WT dams at E18.5. Serum ERFE was mildly elevated from 0.01 to 0.2 ng/mL in iron-replete dams, but substantially elevated from 0.01 to 3.1 ng/mL in iron-deficient dams, similarly to human pregnancy 2. We next assessed iron and hematological parameters in pregnant dams with different Erfe genotypes. Under iron-replete conditions, all three groups had similar serum hepcidin, serum iron and hemoglobin concentrations, but ETg dams had 3-fold higher liver iron than WT and EKO dams, presumably because they are mildly iron-overloaded before pregnancy. On iron-deficient diet, maternal hepcidin was decreased in all three genotypes but more so in ETg dams; however, all three Erfe genotypes had similarly depleted liver iron stores, hypoferremia and anemia. MCV was the only parameter that was decreased in EKO compared to WT dams under both iron conditions. Overall, maternal ERFE played a minor role in regulation of maternal erythropoiesis and iron homeostasis, with the lack of ERFE resulting in smaller RBCs but not anemia. Among embryos, we observed a significant effect of Erfe genotype on embryo hepcidin. ETg embryos had significantly lower liver hepcidin compared to WT embryos under both iron-replete and iron-deficient conditions. Conversely, Erfe KO embryos had higher hepcidin compared to WTs under iron-deficient conditions, indicating that embryo ERFE regulates embryo hepcidin during pregnancy. Under iron-replete conditions however, all three embryo genotypes had similar hematologic parameters, and embryo liver iron was dependent on maternal iron levels, with both ETg and WT embryos from ETg dams having increased liver iron concentrations, indicating that embryo ERFE does not regulate placental iron transfer. Under iron-deficient conditions, there was no difference between ETg and WT embryos in hematological or iron parameters, and both genotypes developed iron deficiency and anemia. However, Erfe KO embryos, which had elevated hepcidin, had maldistribution of iron and worse anemia. EKO embryo liver iron concentrations were 6-fold higher compared to WT iron-deficient embryos, whereas hemoglobin was significantly decreased compared to WT iron-deficient embryos. These findings indicate that under iron-limiting conditions, embryo ERFE is important for the suppression of embryo hepcidin to ensure iron redistribution for embryo erythropoiesis. In summary, during iron replete pregnancy, ERFE plays a minor role in maternal and fetal iron homeostasis and erythropoiesis. However, in response to iron-deficiency anemia during pregnancy, ERFE is important for the redistribution of iron within the embryo to support embryo erythropoiesis. 1Kautz L et al, Nat Genet, 2014 2Delaney K et al, Curr Dev Nutr, 2020 3Coffey R et al, Blood, 2020 Disclosures Ganz: Ambys: Consultancy; Sierra Oncology: Consultancy, Research Funding; Rockwell: Consultancy; Pharmacosmos: Consultancy; Ionis: Consultancy; Protagonist: Consultancy; Intrinsic LifeSciences: Consultancy; RallyBio: Consultancy; Silence Therapeutics: Consultancy; Silarus Pharma: Consultancy; Alnylam: Consultancy; American Regent: Consultancy; Disc Medicine: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZenecaFibrogen: Consultancy; Global Blood Therapeutics: Consultancy; Gossamer Bio: Consultancy; Akebia: Consultancy, Honoraria. Nemeth: Silarus Pharma: Consultancy; Intrinsic LifeSciences: Consultancy; Protagonist: Consultancy; Vifor: Consultancy; Ionis: Consultancy.

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Gastrointestinal metabolism of cadmium in experimental iron deficiency;

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1976.231.2.462 ◽

1976 ◽

Vol 231 (2) ◽

pp. 462-467 ◽

Cited By ~ 63

Author(s):

LS Valberg ◽

J Sorbie ◽

DL Hamilton

Keyword(s):

Molecular Weight ◽

Iron Deficiency ◽

Cadmium Chloride ◽

Cadmium Toxicity ◽

The Body ◽

Toxic Effects ◽

Body Activity ◽

Iron Deficient ◽

Gastrointestinal Uptake ◽

Deficient Mice

The average gastrointestinal uptake 4 h after an intragastric dose of 400 nmol of cadmium chloride labeled with 109CdCl2 in iron-deficient mice, 25%, was significantly greater than the result, 16%, in iron-normal animals, and more cadmium entered the body of the former, 3.8%, than the latter, 2% (P less than 0.05). Between 4 and 72 h, gastrointestinal radioactivity declined without further increase in body activity; however, more radiocadmium remained in the duodenum of iron-deficient than iron-normal animals (P less than 0.05). The radiocadmium sequestered in the duodenum was bound to a protein with a molecular weight of about 12,000. After subcutaneous injection of radiocadmium, the rate of excretion of radioactivity from the body was similar in iron-normal and iron-deficient mice; however, a greater proportion of the injected dose accumulated in the duodenum of the iron-deficient animals (P less than 0.05). Thus, the intestinal adapative response to iron deficiency may enhance cadmium toxicity, whereas sequestration and subsequent excretion of cadmium by the intestinal mucosa serves to protect the body against toxic effects. The duodenum, particularly in iron-deficient mice, is especially vulnerable to the toxic effects of cadmium.

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Gastrin-Deficient Mice Have Disturbed Hematopoiesis in Response to Iron Deficiency

Endocrinology ◽

10.1210/en.2010-1474 ◽

2011 ◽

Vol 152 (8) ◽

pp. 3062-3073 ◽

Cited By ~ 10

Author(s):

Suzana Kovac ◽

Gregory J. Anderson ◽

Warren S. Alexander ◽

Arthur Shulkes ◽

Graham S. Baldwin

Keyword(s):

Iron Deficiency ◽

Acid Secretion ◽

Gastric Acid Secretion ◽

Gastric Acid ◽

Iron Homeostasis ◽

Transferrin Saturation ◽

Deficient Diet ◽

Direct Role ◽

Iron Deficient

Gastrins are peptide hormones important for gastric acid secretion and growth of the gastrointestinal mucosa. We have previously demonstrated that ferric ions bind to gastrins, that the gastrin-ferric ion complex interacts with the iron transport protein transferrin in vitro, and that circulating gastrin concentrations positively correlate with transferrin saturation in vivo. Here we report the effect of long-term dietary iron modification on gastrin-deficient (Gas−/−) and hypergastrinemic cholecystokinin receptor 2-deficient (Cck2r−/−) mice, both of which have reduced basal gastric acid secretion. Iron homeostasis in both strains appeared normal unless the animals were challenged by iron deficiency. When fed an iron-deficient diet, Gas−/− mice, but not Cck2r−/−mice, developed severe anemia. In iron-deficient Gas−/−mice, massive splenomegaly was also apparent with an increased number of splenic megakaryocytes accompanied by thrombocytosis. The expression of the mRNA encoding the iron-regulatory peptide hepcidin, Hamp, was down-regulated in both Cck2r−/− and Gas−/−mice on a low-iron diet, but, interestingly, the reduction was greater in Cck2r−/− mice and smaller in Gas−/− mice than in the corresponding wild-type strains. These data suggest that gastrins play an important direct role, unrelated to their ability to stimulate acid secretion, in hematopoiesis under conditions of iron deficiency.

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Iron Deficiency in Pulmonary Arterial Hypertension: A Deep Dive into the Mechanisms

Cells ◽

10.3390/cells10020477 ◽

2021 ◽

Vol 10 (2) ◽

pp. 477

Author(s):

Marceau Quatredeniers ◽

Pedro Mendes-Ferreira ◽

Diana Santos-Ribeiro ◽

Morad K. Nakhleh ◽

Maria-Rosa Ghigna ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Iron Deficiency ◽

Arterial Hypertension ◽

Iron Homeostasis ◽

Pulmonary Arteries ◽

Right Heart Failure ◽

Deep Dive ◽

Iron Deficient ◽

Pulmonary Arterial ◽

Progressive Occlusion

Pulmonary arterial hypertension (PAH) is a severe cardiovascular disease that is caused by the progressive occlusion of the distal pulmonary arteries, eventually leading to right heart failure and death. Almost 40% of patients with PAH are iron deficient. Although widely studied, the mechanisms linking between PAH and iron deficiency remain unclear. Here we review the mechanisms regulating iron homeostasis and the preclinical and clinical data available on iron deficiency in PAH. Then we discuss the potential implications of iron deficiency on the development and management of PAH.

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Comparison of Apical and Basolateral Cu Treatment for Iron-related Gene Regulation During Deferoxamine Induced Iron Deficiency Anemia

10.21203/rs.3.rs-267161/v1 ◽

2021 ◽

Author(s):

Ezgi Evcan ◽

sukru gulec

Keyword(s):

Tissue Culture ◽

Gene Regulation ◽

Iron Deficiency ◽

Iron Deficiency Anemia ◽

Iron Homeostasis ◽

Deficiency Anemia ◽

Copper Transporter ◽

Culture Plate ◽

Iron Deficient ◽

Basolateral Side

Abstract Background: Intestinal copper transporter (Atp7a) mutant brindled mice with systemic Cu deficiency had elevated Cu levels in enterocyte cells without any perturbation of iron regulating genes, suggesting that blood Cu level might be important for intestinal iron homeostasis during iron deficiency anemia (IDA). We hypothesized that the blood Cu level and polarization (apical and basolateral) of enterocyte cells might be important regulators for the compensatory response on the regulation of genes in enterocyte cells during IDA. Methods: We grew Caco-2 cells on a bicameral cell culture plate to mimic the human intestine system and on a regular tissue culture plate. IDA was induced by Deferoxamine (DFO). The cells were treated with Cu and Cu with Fe following mRNA expressions of DMT1, FPN, TFR, and ANKRD37 were analyzed. Results: Our main finding was that basolateral treatment of Cu significantly reduced mRNA expressions of iron-regulated genes, including DMT1, FPN, TFR, and ANKRD37, compared to DFO treated and DFO with apical Cu treated groups in both bicameral and regular tissue culture plates. Conclusions: Cu level in the basolateral side of Caco-2 cells significantly influenced the intracellular gene regulation in DFO induced iron-deficient condition, and polarization of the cells might be important factor gene regulation in enterocyte cells.

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Serum ceruloplasmin protein expression and activity increases in iron-deficient rats and is further enhanced by higher dietary copper intake

Blood ◽

10.1182/blood-2011-05-352112 ◽

2011 ◽

Vol 118 (11) ◽

pp. 3146-3153 ◽

Cited By ~ 46

Author(s):

Perungavur N. Ranganathan ◽

Yan Lu ◽

Lingli Jiang ◽

Changae Kim ◽

James F. Collins

Keyword(s):

Iron Deficiency ◽

Protein Expression ◽

Iron Homeostasis ◽

Amine Oxidase ◽

Mrna Levels ◽

Hepatic Copper ◽

Liver Copper ◽

Iron Deprivation ◽

Iron Deficient ◽

Expression And Activity

AbstractIncreases in serum and liver copper content are noted during iron deficiency in mammals, suggesting that copper-dependent processes participate during iron deprivation. One point of intersection between the 2 metals is the liver-derived, multicopper ferroxidase ceruloplasmin (Cp) that is important for iron release from certain tissues. The current study sought to explore Cp expression and activity during physiologic states in which hepatic copper loading occurs (eg, iron deficiency). Weanling rats were fed control or low iron diets containing low, normal, or high copper for ∼ 5 weeks, and parameters of iron homeostasis were measured. Liver copper increased in control and iron-deficient rats fed extra copper. Hepatic Cp mRNA levels did not change; however, serum Cp protein was higher during iron deprivation and with higher copper consumption. In-gel and spectrophotometric ferroxidase and amine oxidase assays demonstrated that Cp activity was enhanced when hepatic copper loading occurred. Interestingly, liver copper levels strongly correlated with Cp protein expression and activity. These observations support the possibility that liver copper loading increases metallation of the Cp protein, leading to increased production of the holo enzyme. Moreover, this phenomenon may play an important role in the compensatory response to maintain iron homeostasis during iron deficiency.

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Ferroportin 3 is a dual-targeted mitochondrial/chloroplast iron exporter necessary for iron homeostasis in Arabidopsis

10.1101/2020.07.15.203646 ◽

2020 ◽

Author(s):

Leah J. Kim ◽

Kaitlyn M. Tsuyuki ◽

Fengling Hu ◽

Emily Y. Park ◽

Jingwen Zhang ◽

...

Keyword(s):

Iron Deficiency ◽

Iron Homeostasis ◽

Critical Role ◽

Physiological Role ◽

Chloroplast Ultrastructure ◽

Iron Regulation ◽

Wild Type ◽

Mitochondrial Ultrastructure ◽

Iron Deficient

ABSTRACTMitochondria and chloroplasts are organelles with high iron demand that are particularly susceptible to iron-induced oxidative stress. Despite the necessity of strict iron regulation in these organelles, much remains unknown about mitochondrial and chloroplast iron transport in plants. Here, we propose that Arabidopsis Ferroportin 3 (FPN3) is an iron exporter dual-targeted to mitochondria and chloroplasts. FPN3 is expressed in shoots regardless of iron conditions, but its transcripts accumulate under iron deficiency in roots. fpn3 mutants cannot grow as well as wild type under iron-deficient conditions and shoot iron levels are reduced in fpn3 mutants compared to wild type. ICP-MS measurements show that iron levels in the mitochondria and chloroplasts are increased relative to wild type, consistent with the proposed role of FPN3 as a mitochondrial/plastid iron exporter. In iron deficient fpn3 mutants, abnormal mitochondrial ultrastructure was observed, whereas chloroplast ultrastructure was not affected, implying that FPN3 plays a critical role in the mitochondria. Overall, our study suggests that FPN3 is essential for optimal iron homeostasis.Significance statementIron homeostasis must be tightly controlled in the mitochondria and chloroplasts, but iron trafficking in these organelles is not fully understood. Our work suggests that FPN3 is an iron exporter required for maintaining proper iron levels in mitochondria and chloroplasts. Furthermore, FPN3 is necessary for the optimal growth and normal mitochondrial ultrastructure under iron deficiency. This study reveals the physiological role of FPN3 and advances our understanding of iron regulation in mitochondria and chloroplasts.

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Paracrine Bone Morphogenetic Protein Signaling in Iron Homeostasis

Blood ◽

10.1182/blood-2019-121069 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. SCI-26-SCI-26

Author(s):

Jodie L. Babitt

Keyword(s):

Iron Deficiency ◽

Bone Morphogenetic Protein ◽

Iron Homeostasis ◽

Molecular Mechanisms ◽

Bmp Signaling ◽

Free Oxygen Radicals ◽

Iron Loading ◽

Iron Availability ◽

Bmp Receptors ◽

Morphogenetic Protein

Iron is an essential nutrient that is required not only for hemoglobin production in red blood cells, but also as a co-factor of many other proteins that perform fundamental cellular processes. However, excess iron can generate free oxygen radicals that can be toxic. Cells and organisms have therefore evolved mechanisms to tightly control iron levels. Systemic iron homeostasis is governed by the iron hormone hepcidin that binds and degrades the iron exporter ferroportin to limit iron absorption from dietary sources and iron release from iron-recycling macrophages and hepatocyte stores. The key source of hepcidin that controls systemic iron homeostasis is the liver. Hepcidin production by the liver is coordinated by several signals that communicate the body's iron needs. Increases in serum and tissue iron induce hepcidin production, whereas iron deficiency suppresses hepcidin production, as feedback mechanisms to maintain steady state iron levels. Inflammation induces hepcidin to limit iron availability to infectious organisms that also require iron to grow and proliferate. Increases in erythropoietic drive suppress hepcidin production to increase iron availability for red blood cell production. The bone morphogenetic protein (BMP) signaling pathway is the central signal transduction pathway that controls hepcidin production in the liver. Activation of BMP signaling by iron loading or suppression of BMP signaling by iron deficiency or erythropoietic drive are key mechanisms by which these signals control hepcidin transcription. Iron loading increases production of BMP6 and BMP2 ligands by liver endothelial cells. Endothelial-derived BMP6 and BMP2 have paracrine actions on BMP receptors and the co-receptor hemojuvelin on hepatocytes to phosphorylate SMAD transcription factors, which translocate to the nucleus to regulate hepcidin transcription. Erythropoietic drive increases the production of erythroferrone by erythrocyte precursors. Erythroferrone is secreted into the circulation where it binds BMP ligands to prevent their interaction with cell surface receptors, thereby inhibiting hepcidin transcription. This talk will focus on recent insights into the molecular mechanisms by whch paracrine BMP signaling in the liver coordinates hepcidin production to regulate systemic iron homeostasis. Disclosures Babitt: Ferrumax Pharmaceuticals, Inc: Equity Ownership, Patents & Royalties; Keryx BIopharmaceuticals, Inc (now part of Akebia Therapeutics): Consultancy; Disc Medicine: Consultancy.

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