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.

Influence of Infection/Inflammation, Thalassemia and Nutritional Status on Iron Absorption

2007 ◽  
Vol 77 (3) ◽  
pp. 217-223 ◽  
Author(s):  
Lynch
Keyword(s):  
Iron Homeostasis ◽  
Iron Absorption ◽  
Inflammatory Diseases ◽  
Acid Output ◽  
Peptide Hormone ◽  
Thalassemia Major ◽  
Human Beings ◽  
Iron Release ◽  
Iron Stores ◽  
Gluten Enteropathy

Iron balance in human beings is maintained by the control of absorption. Recent observations have demonstrated that a peptide hormone, hepcidin, is the principal regulator of iron homeostasis. It is produced in the liver in response to increasing iron stores. It is also induced by interleukin-6 (IL-6) in infectious and inflammatory diseases. Hepcidin restricts both iron absorption and iron release from stores. Disorders that affect the duodenum or stomach directly, particularly gluten enteropathy and H. pylori infections, also impair iron absorption by damaging enterocytes or reducing gastric acid output. Hepcidin secretion is suppressed by accelerated erythropoiesis even when iron stores are increased. This appears to account for the contribution that excessive absorption makes to the iron overload seen in patients with iron-loading anemias such as thalassemia major. There is some evidence suggesting that two nutritional deficiency disorders (deficiencies of vitamin A and riboflavin) lead to impaired iron absorption or utilization, but further research is needed to reconcile conflicting experimental observations.

scholarly journals The Relation between Serum Hepcidin, Ferritin, Hepcidin: Ferritin Ratio, Hydroxyurea and Splenectomy in Children with β-Thalassemia

2019 ◽  
Vol 7 (15) ◽  
pp. 2434-2439
Author(s):  
Nagwa Abdallah Ismail ◽  
Sonia Adolf Habib ◽  
Ahmed A. Talaat ◽  
Naglaa Omar Mostafa ◽  
Eman A. Elghoroury
Keyword(s):  
Serum Ferritin ◽  
Iron Homeostasis ◽  
Peptide Hormone ◽  
Thalassemia Major ◽  
Knowing That ◽  
Significant Difference ◽  
Serum Hepcidin ◽  
Effect Of Splenectomy ◽  
Main Regulator ◽  
Beijing China

BACKGROUND: Hepcidin, a small peptide hormone, is established as the main regulator of iron homeostasis. AIM: To estimate serum hepcidin, ferritin, and hepcidin: ferritin ratio in β-thalassemia patients and to determine the effect of splenectomy and hydroxyurea on serum hepcidin. METHODS: A study was conducted on 30 thalassemia major (βTM), 29 thalassemia intermedia (βTI) and 29 healthy children's controls. Data were collected by patient interviewing where detailed history-taking and thorough clinical examinations were carried out. Serum ferritin and hepcidin were measured by ELISA assay (Bioneovan Co. Ltd Beijing, China). RESULTS: Βeta-thalassemia patients had higher serum ferritin, serum hepcidin and lower Hb and hepcidin: ferritin ratio compared to the controls (p < 0.001, 0.010, 0.001, 0.001) respectively. Β-TM patients had higher mean serum hepcidin and serum ferritin compared to β-TI, with statistically significant difference (P = 0.042, P < 0.001, respectively). Twenty-one patients out of 29 βTI was on hydroxyurea therapy; these patients had significantly lower levels of serum ferritin (P < 0.004) and significantly higher levels of Hb (P < 0.004). Serum ferritin was statistically significantly higher in splenectomized patients P < 0.009. Serum hepcidin level was insignificantly higher in splenectomized patients than non-splenectomized patients (21.6 ± 14.75, 17.76 ± 10.01 ng/mL). Hepcidin showed a significantly positive correlation with hepcidin: ferritin ratio in all studied groups. CONCLUSION: Serum hepcidin was elevated in β-thalassemia children with more evident elevation in βTM patients. Splenectomy played no major role in hepcidin regulation. Knowing that hepcidin in serum has a dynamic and multi-factorial regulation, individual evaluation of serum hepcidin and follow up, e.g. every 6 months could be valuable, and future therapeutic hepcidin agonists could be helpful in management of iron burden in such patient.

Hepcidin Expression Is Correlated with Erythropoietic Indexes and Non-Transferrin-Bound Iron Levels in Patients with Thalassemia Major.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2693-2693
Author(s):  
Antonios Kattamis ◽  
Ioannis Papassotiriou ◽  
Danai Palaiologou ◽  
Kalliopi Drakaki ◽  
Filia Apostolopoulou ◽  
...  
Keyword(s):  
Atomic Absorption Spectrometry ◽  
Atomic Absorption ◽  
Iron Absorption ◽  
Transferrin Saturation ◽  
Absorption Spectrometry ◽  
Thalassemia Major ◽  
Erythropoietic Activity ◽  
Hepcidin Expression ◽  
Iron Stores ◽  
Iron Load

Abstract Hepcidin plays a central role in iron homeostasis. Hepcidin seems to be the common final mediator of both erythroid and stores regulators, and coordinates intestinal iron absorption and iron release from reticuloendothelial macrophages. The erythroid regulator probably dominates over the stores regulator. Iron overload in thalassemia major is attributed mainly to blood transfusions and partly to increased iron absorption. Urine hepcidin levels in regularly-transfused thalassemia patients are inappropriately low in regards to their iron stores. Liver hepcidin expression is suppressed in the murine model of human thalassemia (Hbbth3/+). We evaluated the correlation between indexes of iron stores and of erythropoiesis and liver hepcidin expression in patients with thalassemia major. Nineteen transfusion-dependent thalassemic patients (14 females) of 20±7.2 years of age underwent liver biopsy. Fourteen patients were seronegative for hepatitis C. Liver iron concentration (LIC) was estimated by atomic absorption spectrometry. Hepcidin mRNA expression levels were estimated by quantitative Real-Time PCR (Lightcycler, Roche) from isolated RNA from liver tissue. Hematologic and blood chemistry parameters were determined by standard methods. NTBI was measured in 13 patients by atomic absorption spectrometry. Statistical analysis was performed using non-parametric tests. Hepcidin expression ranged from 0.08 to 38.4 (median 1.13) arbitrary units. The most significant correlations between hepcidin and indexes of erythropoesis and of iron load are shown on the table. Variable median (range) hepcidin LIC NTBI r = Spearman’s rho, n.s. = non statistical Ferritin (μg/L) 2174 (990–5963) n.s. n.s. n.s. Hb (g/dL) 12 (11.2 – 13.4) r:0.55, P:.017 r:-0.43, P:.071 n.s. sTfR (mg/L) 2.64 (0.75 – 5.75) r:-0.59, P:.01 r:0.51, P:.03 r:0.71, P:.006 EPO (IU/L) 21.6 (2.9 – 106) r:-0.61, P:.007 r:0.56, P:.015 r:0.63, P:.02 NTBI (μmol/L) 3.1 (0.9 – 4.5) r:0.56, P:.047 r:0.67, P:.012 LIC (μg Fe/d.w.tissue) 8.3 (3.1 – 18.9) n.s. The correlations between hepcidin and Hb, sTfR, EPO were stronger when patients with infectious hepatitis were excluded from analysis. Hepcidin did not correlate with any indexes of iron load, including LIC, ferritin, serum iron, transferrin saturation and annual transfusional iron load. Our results provide additional evidence that increased erythropoietic activity down-regulates hepcidin expression. The lack of correlation between iron stores and hepcidin expression is in consistency with the hypothesis that increased erythropoietic activity dominates over iron stores in the regulation of hepcidin expression in patients with thalassemia major. Furthermore, the negative correlation between NTBI and hepcidin RNA levels underlies the role of hepcidin in iron body trafficking even in hemosiderotic patients.

Molecular basis of iron-loading disorders

2010 ◽  
Vol 12 ◽  
Author(s):  
Deepak Darshan ◽  
David M. Frazer ◽  
Gregory J. Anderson
Keyword(s):  
Iron Homeostasis ◽  
Iron Absorption ◽  
Iron Loading ◽  
Body Iron ◽  
Hepcidin Expression ◽  
Excess Iron ◽  
Iron Trafficking ◽  
Therapeutic Tools ◽  
Export Protein ◽  
Intestinal Enterocytes

Iron-loading disorders (haemochromatosis) represent an important class of human diseases. Primary iron loading results from inherited disturbances in the mechanisms regulating intestinal iron absorption, such that excess iron is taken up from the diet. Body iron load can also be increased by repeated blood transfusions (secondary iron loading), usually as part of the treatment for various haematological disorders. In these syndromes, an element of enhanced iron absorption is also often involved. The central regulator of body iron trafficking is the liver-derived peptide hepcidin. Hepcidin limits iron entry into the plasma from macrophages, intestinal enterocytes and other cells by binding to the sole iron-export protein ferroportin, and facilitating its removal from the plasma membrane. Mutations in hepcidin or its upstream regulators (HFE, TFR2, HFE2 and BMP6) lead to reduced or absent hepcidin expression and a concomitant increase in iron absorption. Mutations in ferroportin that prevent hepcidin binding produce a similar result. Increased ineffective erythropoiesis, which often characterises erythrocyte disorders, also leads to reduced hepcidin expression and increased absorption. Recent advances in our understanding of hepcidin and body iron homeostasis provide the potential for a range of new diagnostic and therapeutic tools for haemochromatosis and related conditions.

scholarly journals Contribution of Hfe expression in macrophages to the regulation of hepatic hepcidin levels and iron loading

Blood ◽  
2005 ◽  
Vol 106 (6) ◽  
pp. 2189-2195 ◽  
Author(s):  
Hortence Makui ◽  
Ricardo J. Soares ◽  
Wenlei Jiang ◽  
Marco Constante ◽  
Manuela M. Santos
Keyword(s):  
Bone Marrow ◽  
Iron Absorption ◽  
Hereditary Hemochromatosis ◽  
Peptide Hormone ◽  
Hfe Gene ◽  
Mrna Levels ◽  
Iron Loading ◽  
Liver Iron ◽  
Hepcidin Expression ◽  
Hepcidin Mrna

Abstract Hereditary hemochromatosis (HH), an iron overload disease associated with mutations in the HFE gene, is characterized by increased intestinal iron absorption and consequent deposition of excess iron, primarily in the liver. Patients with HH and Hfe-deficient (Hfe-/-) mice manifest inappropriate expression of the iron absorption regulator hepcidin, a peptide hormone produced by the liver in response to iron loading. In this study, we investigated the contribution of Hfe expression in macrophages to the regulation of liver hepcidin levels and iron loading. We used bone marrow transplantation to generate wild-type (wt) and Hfe-/- mice chimeric for macrophage Hfe gene expression. Reconstitution of Hfe-deficient mice with wt bone marrow resulted in augmented capacity of the spleen to store iron and in significantly decreased liver iron loading, accompanied by a significant increase of hepatic hepcidin mRNA levels. Conversely, wt mice reconstituted with Hfe-deficient bone marrow had a diminished capacity to store iron in the spleen but no significant alterations of liver iron stores or hepcidin mRNA levels. Our results suggest that macrophage Hfe participates in the regulation of splenic and liver iron concentrations and liver hepcidin expression. (Blood. 2005;106:2189-2195)

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.

scholarly journals The iron-regulatory peptide hormone hepcidin: expression and cellular localization in the mammalian kidney

2005 ◽  
Vol 184 (2) ◽  
pp. 361-370 ◽  
Author(s):  
H Kulaksiz ◽  
F Theilig ◽  
S Bachmann ◽  
S G Gehrke ◽  
D Rost ◽  
...  
Keyword(s):  
Cellular Localization ◽  
Iron Homeostasis ◽  
Apical Cell ◽  
Peptide Hormone ◽  
Thick Ascending Limb ◽  
Divalent Metal Transporter 1 ◽  
Hepcidin Expression ◽  
Mammalian Kidney ◽  
Collecting Ducts ◽  
Tubular System

It is generally accepted that iron homeostasis is mainly controlled in the gastrointestinal tract by absorption of dietary iron. However, recent studies have shown that the kidneys are also involved in iron metabolism. Since the iron-regulatory and antimicrobial peptide hormone hepcidin was originally isolated from human urine we have investigated the expression as well as the zonal and cellular localization of hepcidin in the mammalian kidney and developed an ELISA assay to analyze hepcidin concentrations in serum and urine. The expression of hepcidin was shown by RT-PCR and immunoblot experiments; its cellular localization was studied by immunocytochemistry in human, mouse and rat kidney, which revealed similar patterns of immunoreactivity. Hepcidin expression was absent from the proximal tubule and descending and ascending thin limbs. There was strong expression in the thick ascending limb of the cortex and in connecting tubules. Moderate expression was noted in the thick ascending limb and collecting ducts of the medulla and in collecting ducts of the papilla. Importantly, the cells of the macula densa were unstained. At the cellular level, hepcidin was localized to the apical cell pole of the renal epithelial cells. Based on its presence in urine, hepcidin may be released apically into the urine. Enhanced levels of hepcidin were determined in patients with chronic renal insuffciency (156.8 ng/ml, controls 104.2 ng/ml) indicating that the kidneys may metabolize and/or eliminate the circulating peptide. From the expression of hepcidin in the mammalian kidney, we have concluded that the iron-regulatory hormone is an intrinsic renal peptide which is not only eliminated by the kidney but is also synthesized in the kidney tubular system. Localization of hepcidin in the kidney implicates an iron-regulatory role of this peptide hormone in the renal tubular system, possibly in connection with the iron transporter divalent metal transporter-1.

Reduction of Hepatic Iron in Patients with Thalassemia Major According to Iron Chelation Regime Assessed by MRI T2*

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5410-5410
Author(s):  
Vassilios Ladis ◽  
Giorgos Chouliaras ◽  
Kirikos Zannikos ◽  
Panagiotis Moraitis ◽  
Eleni Berdoussi ◽  
...  
Keyword(s):  
Statistical Significance ◽  
Linear Regression Analysis ◽  
Thalassemia Major ◽  
Rate Of Change ◽  
Hepatic Iron ◽  
Iron Loading ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Iron Load ◽  
Number Of Patients

Abstract In 212 thalassemia major patients, repeated assessments for cardiac and hepatic iron (LIC) assessed by Magnetic Resonance Imaging (MRI – T2*) have been performed. The chelation regimes were either desferrioxamine (DFO), deferiprone (DFP), combination of DFO and DFP (Comb) or deferasirox (DFX). In general over the last few years, tailoring of chelation therapy has been principally guided by the cardiac iron loading. As many patients had been found to have excess cardiac iron, the majority (48%) had been placed on Comb. Patients were grouped according to the degree of siderosis. A T2* of &lt;1.6ms was regarded as heavy LIC, between 1.6–4.0 moderate, 4.1–9.0 mild and &gt; 9.1 acceptable. Taking into account that the change in T2* is not necessarily linear with respect to time and as the overall time of exposure to DFO, DFP and Comb regimes was significantly greater than that with DFX it was unjustified to perform comparative analysis using the total time period of the patients who were on any of the non DFX regimes. Therefore, to compare the efficacy of the four regimes on LIC, we performed an analysis using student T test to assess the rate of change only between the first and second MRI in patients with comparable LIC according to each chelation regime with adjustment for overall time of exposure (Table 1). Using the same data and applying linear regression analysis (Table 2) we compared the effect of DFO to the other three regimes in the annual rate of increasing hepatic T2*. Only Comb is effective at all levels of hepatic iron loading in reducing the iron content. DFX is effective in the mildly iron loaded patients and for the moderately iron loaded patients, its efficacy approaches statistical significance. DFP does not seem to significantly decrease LIC at any level of hepatic iron load however the numbers of patients in that group are very small. Interestingly DFO seems the least effective at all levels of hepatic iron loading and particularly in the heavy loaded patients. This factor may be related to poor compliance to its use as the patients who have reached such levels of iron load are more often those who are not compliant. In the comparison analysis to DFO, only Comb is significantly better and DFP and DFX are equivalent to it. In addition Comb is more effective than DFX and DFP in that over 12 months it would increase the T2* by 3.8ms (p &lt;0.001) and 3.9ms (p 0.012) respectively. DFX and DFP are similar in efficacy in that they maintain the liver iron at the same levels (DFP vDFX 0.009ms p=0.95). In patients with hepatic T2* &gt;9ms, 4 of 11 on DFO, 5 of 6 on DFX, 7 of 11 on DFP and 3 of 22 on Comb fell below 9. It is of note that DFO only maintains LIC and that a number of patients in the normal range increased LIC. Taking this data into account the DFX and DFP results are compatible with those seen both in the clinic and in trials. It is apparent however that combination therapy is the most effective regime for reducing hepatic iron significantly. As with cardiac iron loading, by knowing the degree of hepatic iron loading by the non-invasive T2* measurement and being able to manipulate patients chelation regimes, it seems possible to be able to have patients free of excess hepatic iron and potentially reduce other iron related morbidities as well. Table 1 Annual estimated mean change in T2* according to severity of hepatic siderosis Regime Heavy Moderate Mild ΔT2* p ΔT2** p ΔT2* p *tm= mean time (in months) between MRI studies DFO n= 42 tm*= 24.6 0.05 0.5 0.57 0.37 0.1 0.7 DFP n= 11 tm= 23.8 0.56 0.25 0.88 0.31 3.5 0.19 Comb n= 101 tm=21.7 1.17 0.0064 3.6 &lt;0.001 5.9 &lt;0.001 DFX n=58 tm=15.2 3.1 0.11 1.25 0.06 3.8 0.014 Table 3 Mean estimated difference in T2* Standard Error p DFP v. DFO −0.7 1.6 0.7 Comb v DFO 3.1 1.05 0.03 DFX v DFO −0.7 1.2 0.5

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.

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.

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