scholarly journals Skeletal muscle hemojuvelin is dispensable for systemic iron homeostasis

Blood ◽  
2011 ◽  
Vol 117 (23) ◽  
pp. 6319-6325 ◽  
Author(s):  
Wenjie Chen ◽  
Franklin W. Huang ◽  
Tomasa Barrientos de Renshaw ◽  
Nancy C. Andrews
Keyword(s):  
Skeletal Muscle ◽  
Iron Homeostasis ◽  
Iron Absorption ◽  
Conditional Knockout ◽  
Dietary Iron ◽  
Iron Release ◽  
Hepcidin Expression ◽  
Morphogenetic Protein ◽  
Smad Signaling Pathway ◽  
Very High

Abstract Hepcidin, a hormone produced mainly by the liver, has been shown to inhibit both intestinal iron absorption and iron release from macrophages. Hemojuvelin, a glycophosphatidyl inositol–linked membrane protein, acts as a bone morphogenetic protein coreceptor to activate hepcidin expression through a SMAD signaling pathway in hepatocytes. In the present study, we show in mice that loss of hemojuvelin specifically in the liver leads to decreased liver hepcidin production and increased tissue and serum iron levels. Although it does not have any known function outside of the liver, hemojuvelin is expressed at very high levels in cardiac and skeletal muscle. To explore possible roles for hemojuvelin in skeletal muscle, we analyzed conditional knockout mice that lack muscle hemojuvelin. The mutant animals had no apparent phenotypic abnormalities. We found that systemic iron homeostasis and liver hepcidin expression were not affected by loss of hemojuvelin in skeletal muscle regardless of dietary iron content. We conclude that, in spite of its expression pattern, hemojuvelin is primarily important in the liver.

scholarly journals Molecular mechanisms of normal iron homeostasis

Hematology ◽  
2009 ◽  
Vol 2009 (1) ◽  
pp. 207-214 ◽  
Author(s):  
An-Sheng Zhang ◽  
Caroline A. Enns
Keyword(s):  
Iron Homeostasis ◽  
Molecular Mechanisms ◽  
Iron Absorption ◽  
Hypoxia Inducible Factor ◽  
Bmp Signaling ◽  
Control Mechanisms ◽  
Iron Regulatory Proteins ◽  
Hepcidin Expression ◽  
Cellular Iron ◽  
Morphogenetic Protein

Abstract Humans possess elegant control mechanisms to maintain iron homeostasis by coordinately regulating iron absorption, iron recycling, and mobilization of stored iron. Dietary iron absorption is regulated locally by hypoxia inducible factor (HIF) signaling and iron-regulatory proteins (IRPs) in enterocytes and systematically by hepatic hepcidin, the central iron regulatory hormone. Hepcidin not only controls the rate of iron absorption but also determines iron mobilization from stores through negatively modulating the function of ferroportin, the only identified cellular iron exporter to date. The regulation of hepatic hepcidin is accomplished by the coordinated activity of multiple proteins through different signaling pathways. Recent studies have greatly expanded the knowledge in the understanding of hepcidin expression and regulation by the bone morphogenetic protein (BMP) signaling, the erythroid factors, and inflammation. In this review, we mainly focus on the roles of recently identified proteins in the regulation of iron homeostasis.

scholarly journals Iron metabolism in the hemoglobin-deficit mouse: correlation of diferric transferrin with hepcidin expression

Blood ◽  
2006 ◽  
Vol 107 (4) ◽  
pp. 1659-1664 ◽  
Author(s):  
Sarah J. Wilkins ◽  
David M. Frazer ◽  
Kirstin N. Millard ◽  
Gordon D. McLaren ◽  
Gregory J. Anderson
Keyword(s):  
Iron Absorption ◽  
Transferrin Saturation ◽  
Reticuloendothelial System ◽  
Similar Degree ◽  
Dietary Iron ◽  
Iron Release ◽  
Wild Type ◽  
Hepcidin Expression ◽  
Key Indicator ◽  
Diferric Transferrin

The iron requirements of the erythroid compartment modulate the expression of hepcidin in the liver, which in turn alters intestinal iron absorption and iron release from the reticuloendothelial system. We have taken advantage of an inherited anemia of the mouse (hemoglobin deficit, or hbd) to gain insights into the factors regulating hepcidin expression. hbd mice showed a significant anemia but, surprisingly, their iron absorption was not increased as it was in wild-type animals made anemic to a similar degree by dietary iron depletion. In wild-type mice hepatic hepcidin levels were decreased but in hbd animals a significant and unexpected increase was observed. The level of absorption was appropriate for the expression of hepcidin in each case, but in hbd mice did not reflect the degree of anemia. However, this apparent inappropriate regulation of hepcidin correlated with increased transferrin saturation and levels of diferric transferrin in the plasma, which in turn resulted from the reduced capacity of hbd animals to effectively use transferrin-bound iron. These data strengthen the proposal that diferric transferrin is a key indicator of body iron requirements.

scholarly journals Endothelial cells produce bone morphogenetic protein 6 required for iron homeostasis in mice

Blood ◽  
2017 ◽  
Vol 129 (4) ◽  
pp. 405-414 ◽  
Author(s):  
Susanna Canali ◽  
Kimberly B. Zumbrennen-Bullough ◽  
Amanda B. Core ◽  
Chia-Yu Wang ◽  
Manfred Nairz ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Bone Morphogenetic Protein ◽  
Knockout Mice ◽  
Iron Homeostasis ◽  
Conditional Knockout ◽  
Conditional Knockout Mice ◽  
Morphogenetic Protein ◽  
Key Points ◽  
Paracrine Actions ◽  
Bone Morphogenetic Protein 6

Key Points Endothelial Bmp6 conditional knockout mice exhibit hemochromatosis, whereas hepatocyte and macrophage Bmp6 conditional knockout mice do not. Our data support a model in which EC Bmp6 has paracrine actions on hepatocyte hemojuvelin to regulate hepcidin production.

scholarly journals Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation

Blood ◽  
2011 ◽  
Vol 117 (18) ◽  
pp. 4915-4923 ◽  
Author(s):  
Andrea U. Steinbicker ◽  
Chetana Sachidanandan ◽  
Ashley J. Vonner ◽  
Rushdia Z. Yusuf ◽  
Donna Y. Deng ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Iron Homeostasis ◽  
Iron Bioavailability ◽  
Bmp Signaling ◽  
Neoplastic Disease ◽  
Type I ◽  
Hepcidin Expression ◽  
Hepatic Expression ◽  
Morphogenetic Protein ◽  
Anemia Of Inflammation

Abstract Anemia of inflammation develops in settings of chronic inflammatory, infectious, or neoplastic disease. In this highly prevalent form of anemia, inflammatory cytokines, including IL-6, stimulate hepatic expression of hepcidin, which negatively regulates iron bioavailability by inactivating ferroportin. Hepcidin is transcriptionally regulated by IL-6 and bone morphogenetic protein (BMP) signaling. We hypothesized that inhibiting BMP signaling can reduce hepcidin expression and ameliorate hypoferremia and anemia associated with inflammation. In human hepatoma cells, IL-6–induced hepcidin expression, an effect that was inhibited by treatment with a BMP type I receptor inhibitor, LDN-193189, or BMP ligand antagonists noggin and ALK3-Fc. In zebrafish, the induction of hepcidin expression by transgenic expression of IL-6 was also reduced by LDN-193189. In mice, treatment with IL-6 or turpentine increased hepcidin expression and reduced serum iron, effects that were inhibited by LDN-193189 or ALK3-Fc. Chronic turpentine treatment led to microcytic anemia, which was prevented by concurrent administration of LDN-193189 or attenuated when LDN-193189 was administered after anemia was established. Our studies support the concept that BMP and IL-6 act together to regulate iron homeostasis and suggest that inhibition of BMP signaling may be an effective strategy for the treatment of anemia of inflammation.

Myocardial iron homeostasis and hepcidin expression in a rat model of heart failure at different levels of dietary iron intake

2019 ◽  
Vol 1863 (4) ◽  
pp. 703-713 ◽  
Author(s):  
Jiri Petrak ◽  
Tereza Havlenova ◽  
Matyas Krijt ◽  
Matej Behounek ◽  
Janka Franekova ◽  
...  
Keyword(s):  
Heart Failure ◽  
Rat Model ◽  
Iron Homeostasis ◽  
Dietary Iron ◽  
Myocardial Iron ◽  
Iron Intake ◽  
Hepcidin Expression ◽  
Different Levels

scholarly journals Hepcidin: A Critical Regulator of Iron Metabolism during Hypoxia

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Korry J. Hintze ◽  
James P. McClung
Keyword(s):  
Iron Metabolism ◽  
Iron Homeostasis ◽  
Molecular Mechanisms ◽  
Iron Absorption ◽  
Iron Acquisition ◽  
Iron Status ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Response Element ◽  
Hypoxia Response ◽  
Hepcidin Expression

Iron status affects cognitive and physical performance in humans. Recent evidence indicates that iron balance is a tightly regulated process affected by a series of factors other than diet, to include hypoxia. Hypoxia has profound effects on iron absorption and results in increased iron acquisition and erythropoiesis when humans move from sea level to altitude. The effects of hypoxia on iron balance have been attributed to hepcidin, a central regulator of iron homeostasis. This paper will focus on the molecular mechanisms by which hypoxia affects hepcidin expression, to include a review of the hypoxia inducible factor (HIF)/hypoxia response element (HRE) system, as well as recent evidence indicating that localized adipose hypoxia due to obesity may affect hepcidin signaling and organismal iron metabolism.

Cell surface serine protease matriptase-2 suppresses fetuin-A/AHSG-mediated induction of hepcidin

2015 ◽  
Vol 396 (1) ◽  
pp. 81-93 ◽  
Author(s):  
Marit Stirnberg ◽  
Eva Maurer ◽  
Katharina Arenz ◽  
Anne Babler ◽  
Willi Jahnen-Dechent ◽  
...  
Keyword(s):  
Serine Protease ◽  
Iron Homeostasis ◽  
Mrna Levels ◽  
Fetuin A ◽  
Hepcidin Expression ◽  
Morphogenetic Protein ◽  
Protease Substrate ◽  
Transmembrane Serine Protease ◽  
Chain Form

Abstract Matriptase-2 is a type II transmembrane serine protease controlling the expression of hepcidin, the key regulator of iron homeostasis. By cleaving hemojuvelin, matriptase-2 suppresses bone morphogenetic protein/sons of mothers against decapentaplegic signaling. So far, the only known putative substrates of matriptase-2 are hemojuvelin and matriptase-2 itself. In this study, fetuin-A (α2-Heremans-Schmid glycoprotein) was identified in vitro as a substrate of matriptase-2. The protease–substrate interaction was validated by isolating matriptase-2 via the affinity to fetuin-A. Fetuin-A is a liver-derived plasma protein with multiple functions, which is proteolytically processed to yield a disulfide-linked two-chain form. In co-transfected cells, a matriptase-2-dependent conversion of unprocessed fetuin-A into a two-chain form was detected. Conversely, downregulation of endogenously expressed matriptase-2 stabilized fetuin-A. Arg and Lys residues located within the 40 residue spanning connecting peptide of fetuin-A were identified as cleavage sites for matriptase-2. Analysis of hepcidin expression revealed an inductive effect of fetuin-A, which was abolished by matriptase-2. Fetuin-A deficiency in mice resulted in decreased hepcidin mRNA levels. These findings implicate a role of fetuin-A in iron homeostasis and provide new insights into the mechanism of how matriptase-2 might modulate hepcidin expression.

Dietary Supplementation with Genistein Increases Hepcidin Expression in Wild Type Mice

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3208-3208
Author(s):  
Aileen W. Zhen ◽  
Josephine Volovetz ◽  
Paula G. Fraenkel
Keyword(s):  
Iron Overload ◽  
Iron Content ◽  
Iron Absorption ◽  
Small Scale ◽  
Iron Release ◽  
Liver Iron ◽  
Transcript Levels ◽  
Intestinal Iron Absorption ◽  
Hepcidin Expression ◽  
Liver Iron Content

Abstract Abstract 3208 Iron overload is an important cause of morbidity and death in patients with hemoglobinopathies, transfusion-dependent anemias, and hereditary hemochromatosis. As humans have no means of excreting iron, regulation of iron homeostasis depends on limiting intestinal iron absorption and optimizing iron release from macrophages to developing erythrocytes. Hepcidin, a peptide hormone produced in the liver, modulates intestinal iron absorption and macrophage iron release via effects on ferroportin. Hepcidin is a potential drug target for patients with iron overload syndromes because its levels are inappropriately low in these individuals. We conducted a small-scale chemical screen and found that the isoflavone genistein, a major dietary component of soybeans, enhanced Hepcidin transcript levels in zebrafish embryos. Furthermore genistein treatment increased Hepcidin transcript levels and Hepcidin promoter activity in human hepatocytes (HepG2 cells) in a Stat3 and Smad4-dependent manner. To evaluate genistein's effect in a mammalian model, we placed groups of 4 four-week old male C57BL/6 mice on an iron-sufficient, low soy diet (AIN93G containing 35 mg of iron/kg) supplemented with 0, 250, or 500 mg of genistein per kg of food for 7 weeks, and then sacrificed the animals for analysis. Plasma genistein levels (mean±SE) at the time of sacrifice were 0.015±0.015, 0.52±0.173, and 2.07±0.65 micromolar, respectively. Compared to mice not treated with genistein, the 250 mg/kg dose produced a significant increase in hepatic Hepcidin (HAMP1) transcript levels (1.49±0.10 vs 0.93±0.10, p=0.01), while the 500 mg/kg dose did not. Although liver iron content, spleen iron content, and weight gain were not significantly different among the groups, the ratio of Hepcidin expression to liver iron content was significantly increased in the animals treated with genistein 250 mg/kg compared to controls (0.013±0.0009 vs 0.0074±0.00068, p=0.0068). In conclusion, genistein is the first orally administered small molecule experimental drug shown to increase Hepcidin transcript levels in vivo. Future experiments will evaluate the effects of genistein on genetic models of iron overload syndromes. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Contribution of STAT3 and SMAD4 pathways to the regulation of hepcidin by opposing stimuli

Blood ◽  
2009 ◽  
Vol 113 (15) ◽  
pp. 3593-3599 ◽  
Author(s):  
Hua Huang ◽  
Marco Constante ◽  
Antonio Layoun ◽  
Manuela M. Santos
Keyword(s):  
Chronic Disease ◽  
Iron Absorption ◽  
Dependent Manner ◽  
Dietary Iron ◽  
Iron Loading ◽  
Anemia Of Chronic Disease ◽  
Hepcidin Expression ◽  
The Individual ◽  
Dose Dependent

Abstract Hepcidin, a key regulator of iron metabolism, is a small antimicrobial peptide produced by the liver that regulates intestinal iron absorption and iron recycling by macrophages. Hepcidin is stimulated when iron stores increase and during inflammation and, conversely, is inhibited by hypoxia and augmented erythropoiesis. In many pathologic situations, such as in the anemia of chronic disease (ACD) and iron-loading anemias, several of these factors may be present concomitantly and may generate opposing signaling to regulate hepcidin expression. Here, we address the question of dominance among the regulators of hepcidin expression. We show that erythropoiesis drive, stimulated by erythropoietin but not hypoxia, down-regulates hepcidin in a dose-dependent manner, even in the presence of lipopolysaccharide (LPS) or dietary iron-loading, which may act additively. These effects are mediated through down-regulation of phosporylation of Stat3 triggered by LPS and of Smad1/5/8 induced by iron. In conclusion, hepcidin expression levels in the presence of opposing signaling are determined by the strength of the individual stimuli rather than by an absolute hierarchy among signaling pathways. Our findings also suggest that erythropoietic drive can inhibit both inflammatory and iron-sensing pathways, at least in part, via the suppression of STAT3 and SMAD4 signaling in vivo.

Urinary Hepcidin in Thalassemic Syndromes.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3589-3589
Author(s):  
Elizabeta Nemeth ◽  
Raffaella Origa ◽  
Tomas Ganz ◽  
Renzo Galanello
Keyword(s):  
Iron Homeostasis ◽  
Iron Absorption ◽  
Peptide Hormone ◽  
Thalassemia Major ◽  
Iron Loading ◽  
Hepcidin Expression ◽  
Amino Acid Peptide ◽  
Iron Load ◽  
Main Regulator ◽  
One Way Anova

Abstract Hepcidin, a 25 amino-acid peptide hormone synthesized in the liver, is the key regulator of iron homeostasis. Hepcidin inhibits intestinal iron absorption, recycling of iron in the macrophages and mobilization of iron from hepatic stores. Hepcidin expression is induced by iron loading and inflammation and is suppressed by anemia and hypoxia, but the relative influences of these modifiers are not well understood. Thalassemia syndromes represent a clinical setting where hepcidin is regulated by opposing influences of ineffective erythropoiesis and elevated iron load. We evaluated urinary hepcidin levels in 10 thalassemia intermedia (TI) patients who had no or very few transfusions (less than 5, and all completed more than 15 years ago), and 11 thalassemia major (TM) patients who were regularly transfused and iron chelated. All patients had beta-zero thalassemia (beta 39C→G non-sense mutation). When compared to the unrelated controls, urinary hepcidin was decreased in TI and increased in TM [median (interquartile range) in ng hepcidin/mg creatinine: controls 44 (27–66); TI 6 (5–9); TM 218 (116–470); all comparisons p<0.001 by One Way ANOVA with Dunn’s]. However, assessment of the hepcidin-to-ferritin ratio, an index of the appropriateness of hepcidin expression relative to the degree of iron loading, showed that the ratio was low in both thalassemia syndromes when compared to controls. The result suggests that even in TM patients, hepcidin is inappropriately low relative to the patients’ iron load. Importantly, in TM when measured over 1 week, hepcidin levels decreased in correlation with the patients’ rapidly decreasing Hb levels. In considering all the thalassemia patients together, urinary hepcidin levels correlated positively with serum ferritin and hemoglobin, and negatively with sTfR and serum erythropoetin. Multivariate analysis showed the strongest correlation with sTfR (r2=0.83). The results indicate that in TI, the strong erythropoietic drive is the main regulator of hepcidin. The resulting hepcidin deficiency may be the cause of the increased iron absorption in TI. In TM, transfusions partially relieve the erythropoetic drive and increase the iron loading of macrophages thus raising hepcidin levels above those seen in TI. In the future, therapeutic use of hepcidin could restore normal iron homeostasis in some thalassemics, especially those not requiring transfusions.

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