Blood online
Home About Blood Authors Subscriptions Permission Advertising Public Access contact us
 

 
Advanced
Current Issue
First Edition
Future Articles
Archives
Submit to Blood
Search
American Society of Hematology
Meeting Abstracts
Email Alerts
 Prepublished online as a Blood First Edition Paper on March 13, 2003; DOI 10.1182/blood-2002-11-3610.

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
2002-11-3610v1
102/1/371    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Right arrow Rights and Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gehrke, S. G.
Right arrow Articles by Stremmel, W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gehrke, S. G.
Right arrow Articles by Stremmel, W.
Related Collections
Right arrow Red Cells
Right arrow Gene Expression
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

arrow to previous article Previous Article  |  Table of Contents  |  Next Article next article arrow

Blood, 1 July 2003, Vol. 102, No. 1, pp. 371-376

RED CELLS

Expression of hepcidin in hereditary hemochromatosis: evidence for a regulation in response to the serum transferrin saturation and to non-transferrin-bound iron

Sven G. Gehrke, Hasan Kulaksiz, Thomas Herrmann, Hans-Dieter Riedel, Karin Bents, Claudia Veltkamp, and Wolfgang Stremmel

From the Department of Internal Medicine IV, University Hospital Heidelberg, Germany.


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Experimental data suggest the antimicrobial peptide hepcidin as a central regulator in iron homeostasis. In this study, we characterized the expression of human hepcidin in experimental and clinical iron overload conditions, including hereditary hemochromatosis. Using quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), we determined expression of hepcidin and the most relevant iron-related genes in liver biopsies from patients with hemochromatosis and iron-stain-negative control subjects. Regulation of hepcidin mRNA expression in response to transferrin-bound iron, non-transferrin-bound iron, and deferoxamine was analyzed in HepG2 cells. Hepcidin expression correlated significantly with serum ferritin levels in controls, whereas no significant up-regulation was observed in patients with hemochromatosis despite iron-overload conditions and high serum ferritin levels. However, patients with hemochromatosis showed an inverse correlation between hepcidin transcript levels and the serum transferrin saturation. Moreover, we found a significant correlation between hepatic transcript levels of hepcidin and transferrin receptor-2 irrespective of the iron status. In vitro data indicated that hepcidin expression is down-regulated in response to non-transferrin-bound iron. In conclusion, the presented data suggest a close relationship between the transferrin saturation and hepatic hepcidin expression in hereditary hemochromatosis. Although the causality is not yet clear, this interaction might result from a down-regulation of hepcidin expression in response to significant levels of non-transferrin-bound iron. (Blood. 2003;102:371-376)


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Abnormal iron homeostasis is found in many common disorders. These disorders include the iron storage disease, hereditary hemochromatosis, chronic viral hepatitis, alcoholic liver disease, chronic inflammation, or anemias with ineffective erythropoiesis such as thalassemia.1-5

Although several new elements of iron metabolism have been characterized over the past years, for most disorders the exact pathophysiology of iron overload is still unclear. It has been shown that the limiting step in iron homeostasis, the intestinal absorption of dietary ferrous Fe[II] iron, seems to be mediated by 2 iron transport proteins. Dietary Fe[II] is transported into the enterocytes by the apical transporter divalent metal ion transporter 1 (DMT1; formerly called Nramp2, DCT1).6,7 The basolateral transporter iron-regulated transporter 1 (IREG1; also known as ferroportin, MTP1) stimulates iron efflux and, therefore, might export the absorbed Fe[II] from the enterocyte into the plasma.8-10 Most absorbed plasma iron then binds to transferrin and circulates as diferric transferrin (Fe[III]2-Tf).11,12 In addition, a small proportion of iron exported into the plasma is found as non-transferrin-bound iron (NTBI).13

Most of the absorbed iron is used in the bone marrow, where transferrin-bound iron is needed for erythropoiesis and taken up by the classical transferrin receptor 1 (TfR1) pathway. The excess iron is stored in the liver.2,11,12 This cellular iron uptake mechanism might also include the identified transferrin-receptor 2 (TfR2) that shows a high hepatic expression.14-16

The transferrin receptor pathway seems to play a central role in the pathogenesis of the most common iron storage disease, hereditary hemochromatosis. This disorder is associated with a homozygous Cys282Tyr mutation in the hemochromatosis gene HFE.17 The HFE protein is homologous to class I major histocompatibility complex (MHC) molecules and requires {beta}2-microglobulin ({beta}2m) for surface presentation.17-19 Experimental studies have shown that isolated overexpression of wild-type HFE leads to a decreased cellular uptake of transferrin-bound iron by binding to homodimeric TfR1 and lowering the affinity for iron-saturated transferrin.20,21 However, coexpression of both wild-type HFE and {beta}2m has the reverse effect and results in an increase in TfR1-dependent cellular iron uptake.22

The Cys282Tyr substitution in HFE disrupts the association with {beta}2m and, therefore, prevents surface presentation of HFE.18,19 Although the exact mechanism is still incompletely understood, the homozygous Cys282Tyr mutation is associated with an increased intestinal iron absorption, resulting in parenchymal iron overload and the clinical syndrome of hemochromatosis.23

A phenotype similar to classical hereditary hemochromatosis is also observed in individuals with mutations in TfR2 (hemochromatosis type 3)24,25 or IREG1 (autosomal dominant hemochromatosis; type 4).26,27 An identified antimicrobial peptide, named hepcidin, represents another strong candidate putatively involved in the etiology of iron overload syndromes.28-30 Such a hypothesis is supported by the observation that a hepcidin knockout leads to severe iron overload and a hepcidin overexpression to severe iron deficiency.31-33 In addition, hepcidin mutations were found in 2 families with a new type of juvenile hemochromatosis not linked to chromosome 1q.34

Because hepcidin is induced by iron stores30,35 and inflammation,36,37 it might act as a central iron-regulatory hormone important in the pathogenesis of iron overload and the anemia of chronic disease. Therefore, the aim of the present study was to evaluate the regulation of hepcidin in response to iron loading and its role in hereditary hemochromatosis.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Cells

HepG2 cells were obtained from DSMZ (Braunschweig, Germany) and grown in RPMI 1640 medium containing 10% fetal calf serum, penicillin (100 U/mL), and streptomycin (100 µg/mL). Incubation was performed with 65 µM Fe-NTA (1:1), 50 µM deferoxamine (DFO), and 2.5 g/L iron-saturated human diferric transferrin (Fe[III]2-Tf).

Liver biopsies

Liver biopsy samples, obtained for diagnostic purposes, were from 10 patients with iron-overloaded hereditary hemochromatosis (HH) homozygous for the Cys282Tyr mutation in HFE prior to phlebotomy. Control samples derived from 20 patients (7 with isolated {gamma}-glutamyl transferase elevation and healthy liver histology, 2 with mild steatosis, and 11 with chronic hepatitis C and mild histological activity) (Table 1). All control samples showed no significant fibrosis and were negative for stainable iron in liver biopsy. Samples were stored at -20°C in RNAlater solution (Ambion, Austin, TX) prior to RNA isolation. The study was approved by the local ethics committee of the University of Heidelberg. Informed consent was obtained from all patients.


View this table:
[in this window]
[in a new window]
  		Table 1.. Demographic characteristics and iron parameters of patients with hemochromatosis and control individuals

 

Chemicals

RPMI 1640 medium, penicillin, and streptomycin were from Life Technologies (Paisley, United Kingdom). Ferric nitrate nonahydrate, nitrilotriacetic acid disodium salt (NTA), and iron-saturated diferric transferrin were obtained from Sigma-Aldrich (Steinheim, Germany). Deferoxamine was from Novartis (Nuernberg, Germany).

Determination of serum iron parameters

Serum ferritin levels were measured by electrochemiluminescence immunoassay (ECLIA) technology on an Elecsys analyzer (Roche Diagnostics, Mannheim, Germany). Transferrin saturation was calculated from serum iron, determined photometrically on an LX-Analyzer (Beckman-Coulter, Krefeld, Germany), and serum transferrin, determined by nephelometry on a BNAII analyzer (Dade-Behring, Schwalbach, Germany), as iron (µg/dL) x 100/transferrin (mg/dL) x 1.4. Serum samples were obtained in the fasting state at the same time of day.

Quantitative RT-PCR

Total RNA was isolated from liver biopsies and from cell culture using the RNAeasy Mini Kit (Qiagen, Hilden, Germany) including DNAse digestion according to manufacturer's instructions. Real-time quantification of mRNA transcripts was performed with a 2-step reverse transcriptase-polymerase chain reaction (RT-PCR) using the LightCycler system and Relative Quantification Software Version 1.0 (Roche Molecular Biochemicals, Mannheim, Germany). In a first step, cDNA synthesis was performed with the First Strand cDNA Synthesis Kit for RT-PCR (Roche Molecular Biochemicals) according to manufacturer's instructions. In a second step, transcripts of hepcidin (Hepc), transferrin receptor (TfR1), transferrin receptor-2 (TfR2), iron-regulated transporter (IREG1), the IRE and non-IRE splice variant of the divalent metal-ion transporter (DMT1-IRE, DMT1-nonIRE), and ceruloplasmin (Cp) were amplified in duplicates with specific sense and antisense primers (Table 2). All transcripts were detected using SYBR Green I according to manufacturer's instructions and were normalized to actin ({beta}-actin) as internal control. Therefore, actin transcripts were amplified in duplicates with sense primer ACTB-502 (5'-AGG ATG CAG AAG GAG ATC ACT G) and antisense primer ACTB-302 (5'-GGG TGT AAC GCA ACT AAG TCA TAG) and detected using SYBR Green I. Hepc/Actin, TfR1/Actin, TfR2/Actin, IREG1/Actin, DMT1-IRE/Actin, DMT1-nonIRE/Actin, and Cp/Actin ratios were calculated using LightCycler Relative Quantification Software Version 1.0 (Roche Molecular Biochemicals), which provides a fully automated, efficiency-corrected, relative quantification normalized to calibrators. According to manufacturer's instructions, calibrators for Hepc, TfR1, TfR2, IREG1, DMT1-IRE, DMT1-nonIRE, Cp, and {beta}-actin were generated from expressed sequence tag (EST) clones (obtained from RZPD, Berlin, Germany, followed by sequence analyses to verify the proposed insert). In addition, standard curves were prepared according to accurately determined dilutions of the plasmids containing cDNA sequences of Hepc, TfR1, TfR2, IREG1, DMT1-IRE, DMT1-nonIRE, Cp, and {beta}-actin as templates. Plasmid dilutions covered a dynamic range of 5 logarithmic orders.


View this table:
[in this window]
[in a new window]
  		Table 2.. Primers for quantification of Hepc, TfR1, TfR2, IREG1, DMT1-IRE, DMT1-nonIRE, and Cp transcripts using the LightCycler RT-PCR assay

 

Statistical analysis

Statistical analysis of quantitative variables was performed using the nonparametric Mann-Whitney test. To study the linear relationship between continuous variables, Pearson correlation coefficients were calculated. P < .05 was considered significant. All statistical analyses were performed using StatView Version 5.0 (SAS Institute, Cary, NC).


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Transcript levels of iron-related genes in liver biopsies from patients with HH and iron-stain-negative control subjects

Hepatic expression of the iron-related genes Hepc, TfR1, TfR2, IREG1, DMT1-IRE, DMT1-nonIRE, and Cp normalized to actin transcript levels was analyzed in liver biopsy samples from patients with untreated hereditary hemochromatosis and in liver biopsy samples from control individuals negative for iron staining (Table 1). Differences between patients with HH and control subjects were found for the mean TfR1/Actin ratio. As expected, the TfR1/Actin ratio was significantly decreased in patients with untreated HH (P < .001) (Figure 1). In contrast, mean ratios (± standard deviation) for Hepc/Actin (0.53 ± 0.26 versus 0.47 ± 0.52) (Figure 1), TfR2/Actin (0.90 ± 0.37 versus 0.73 ± 0.18), IREG1/Actin x 10 (1.35 ± 0.30 versus 1.27 ± 0.26), DMT1-IRE/Actin x 102 (0.99 ± 0.56 versus 0.87 ± 0.49), DMT1-nonIRE/Actin x 102 (3.45 ± 0.72 versus 4.62 ± 1.75), and Cp/Actin (0.50 ± 0.21 versus 0.62 ± 0.24) did not differ significantly between patients with HH and control subjects.



View larger version (14K):
[in this window]
[in a new window]
  		Figure 1.. Hepatic TfR1/Actin x 103 and Hepc/Actin ratios in patients with HH and control individuals. The mean values are shown (± 95% confidence intervals). The TfR1/Actin x 103 ratio differed significantly between patients with HH and control individuals (P < .001).

 

Hepatic expression of hepcidin in relation to serum ferritin levels and the transferrin saturation

In control individuals, the hepatic Hepc/Actin ratio correlated significantly with serum ferritin levels (r = 0.713, P < .001) (Figure 2A). In contrast, an inverse correlation between the hepatic Hepc/Actin ratio and serum ferritin levels was observed in patients with iron overloaded HH (r = -0.715, P < .05) (Figure 2B). We also analyzed the association between the hepatic Hepc/Actin ratio and the serum transferrin saturation. Patients with HH with a transferrin saturation above 80% showed a strong inverse correlation between the Hepc/Actin ratio and the serum transferrin saturation (r = -0.861, P < .01) (Figure 3B); no significant correlation was found in control patients with a transferrin saturation between 4% and 51% (Figure 3A).



View larger version (13K):
[in this window]
[in a new window]
  		Figure 2.. Linear regression analysis of the correlation between the hepatic Hepc/Actin ratio and serum ferritin levels in control individuals and untreated HH patients. (A) In control individuals, the hepatic Hepc/Actin ratio correlated significantly with serum ferritin levels. (B) In iron overloaded HH patients, an inverse correlation between the hepatic Hepc/Actin ratio and serum ferritin levels was observed. * indicates statistically significant using multiple regression analysis (serum ferritin levels and serum transferrin saturation).

 


View larger version (14K):
[in this window]
[in a new window]
  		Figure 3.. Linear regression analysis of the correlation between the hepatic Hepc/Actin ratio and the serum transferrin saturation in control individuals and untreated HH patients. (A) In control patients, no significant correlation between the hepatic Hepc/Actin ratio and the serum transferrin saturation was found. (B) HH patients with a transferrin saturation above 80% showed a strong inverse correlation between the Hepc/Actin ratio and the serum transferrin saturation. * indicates statistically significant using multiple regression analysis (serum ferritin levels and serum transferrin saturation).

 

Because the hepatic Hepc/Actin ratio was found to correlate with serum ferritin levels and the transferrin saturation, multiple regression analyses were performed. These analyses confirmed the significant correlation between the Hepc/Actin ratio and serum ferritin levels in control individuals (P < .001) (Figure 2A) and the significant inverse correlation between the Hepc/Actin ratio and the serum transferrin saturation in patients with untreated HH (P < .05) (Figure 3B). The inverse correlation between the Hepc/Actin ratio and serum ferritin levels in patients with HH (Figure 2B) did not remain statistically significant using multiple regression analysis. As the serum ferritin levels correlate with the serum transferrin saturation in our patients with HH (r = 0.662, P < .05), the impaired Hepc/Actin ratio in patients with HH with high serum ferritin levels (Figure 2B) might be indeed related to a high transferrin saturation.

Hepatic Hepc/Actin ratio correlates significantly with the hepatic TfR2/Actin ratio

To evaluate whether the expression of hepcidin in liver correlates with the expression of iron-related genes, Hepc/Actin ratios of all patients (control subjects and patients with HH) were plotted against TfR1/Actin, TfR2/Actin, IREG1/Actin, DMT1-IRE/Actin, DMT1-nonIRE/Actin, and Cp/Actin ratios. These analyses revealed a strong correlation between the Hepc/Actin ratio and the TfR2/Actin ratio (r = 0.777, P < .0001) (Figure 4). In addition, data from control subjects and patients with HH were analyzed separately. These analyses also demonstrated a significant correlation between the Hepc/Actin ratio and the TfR2/Actin ratio in control subjects (r = 0.636, P = .014) and patients with HH (r = 0.823, P < .01). However, no significant correlation between the Hepc/Actin ratio and TfR1/Actin, IREG1/Actin, DMT1-IRE/Actin, DMT1-nonIRE/Actin, and Cp/Actin ratios was found in patients with HH and control subjects.



View larger version (11K):
[in this window]
[in a new window]
  		Figure 4.. Linear regression analysis of the correlation between the hepatic Hepc/Actin ratio and the hepatic TfR2/Actin ratio in control individuals and patients with HH.

 

Hepcidin is down-regulated in HepG2 cells in response to non-transferrin-bound iron but not in response to diferric transferrin

For in vitro analysis of hepcidin regulation in response to iron, HepG2 cells were incubated for 72 hours with different concentrations of non-transferrin-bound ferric iron (Fe-NTA). As demonstrated in Figure 5, the Hepc/Actin ratio decreased after incubation with Fe-NTA in a concentration-dependent manner. Fe-NTA led to a significant reduction of the Hepc/Actin ratio at a minimum concentration of 10 µM (P < .01). This down-regulation of hepcidin transcripts was specific for Fe[III], as 65 µM Fe[III] sorbitol citrate produced comparable results, and 65 µM NTA had no effect on the Hepc/Actin ratio (data not shown). To evaluate whether down-regulation of hepcidin is restricted to non-transferrin-bound iron, HepG2 cells were incubated for 24 hours with 65 µM Fe-NTA or 2.5 g/L iron-saturated, human, differic transferrin (equivalent to 65 µM transferrin-bound Fe[III]). As a positive control, the TfR1/Actin ratio was measured. Although incubation with 50 µM deferoxamine resulted in a significant up-regulation of TfR1 transcripts, incubation with 2.5 g/L diferric transferrin and 65 µM Fe-NTA led to a significantly decreased TfR1/Actin ratio (Figure 6A). The Hepc/Actin ratio significantly decreased after incubation with 65 µM Fe-NTA, whereas incubation with 2.5 g/L diferric transferrin had no effect (Figure 6B), indicating that down-regulation of hepcidin is restricted to non-transferrin-bound iron.



View larger version (13K):
[in this window]
[in a new window]
  		Figure 5.. Hepc/Actin ratios in HepG2 cells after incubation with increasing concentrations of Fe-NTA for 72 hours. The results (mean values ± 95% confidence intervals) of 7 independent experiments are shown. The decrease in the Hepc/Actin ratio was statistically significant (P < .01) at a minimum concentration of 10 µM Fe-NTA.

 


View larger version (11K):
[in this window]
[in a new window]
  		Figure 6.. TfR1/Actin x 102 and Hepc/Actin ratios in HepG2 cells after incubation with 50 µM deferoxamine, 2.5 g/L iron saturated diferric transferrin (equivalent to 65 µM transferrin-bound Fe[III]), and 65 µM Fe-NTA (equivalent to 65 µM non-transferrin-bound Fe[III]) for 24 hours. The results (mean values ± 95% confidence intervals) of 8 independent experiments are shown. (A) The increase of the TfR1/Actin x 102 ratio after incubation with 50 µM deferoxamine and the decrease of the TfR1/Actin x 102 ratio after incubation with 2.5 g/L iron-saturated diferric transferrin and 65 µM Fe-NTA was statistically significant (P < .01). (B) The decrease of the Hepc/Actin ratio after incubation with 65 µM Fe-NTA was also statistically significant (P < .001).

 


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
Previous data indicate that hepcidin mRNA increases in response to exogenous iron loading and is 2-fold up-regulated in {beta}2-microglobulin knockout mice, a model of spontaneous iron loading resembling HH.30 In addition, Nicolas et al31 demonstrated a severe iron overload in hepcidin-deficient mice and showed that transgenic mice expressing liver hepcidin develop severe iron-deficiency anemia.32 Interestingly, identical findings have been recently demonstrated in patients carrying nonsense mutations in the hepcidin gene and in patients with hepatic adenomas that produce inappropriately high levels of hepcidin. Although hepcidin mutations are associated with a new type of severe juvenile hemochromatosis not related to chromosome 1q,34 patients with adenomas expressing hepcidin developed iron-refractory anemia that spontaneously resolved after resection of the adenomas.33 On the basis of these observations, hepcidin represents a strong candidate for a regulatory peptide maintaining iron homeostasis, most likely by down-regulation of intestinal iron absorption.38,39

As the role of hepcidin in HH is still unknown, we investigated hepatic expression of hepcidin mRNA in patients with untreated HH and iron-stain-negative control subjects using quantitative RT-PCR. In control individuals, we found a positive correlation between hepatic hepcidin expression and serum ferritin levels. Although this positive correlation suggests an association between hepcidin expression and increased iron stores, we could not demonstrate an up-regulation of hepcidin expression in patients with iron overloaded HH. However, in patients with untreated HH with transferrin saturations above 80% we found a strong inverse correlation between the hepatic hepcidin expression and the serum transferrin saturation.

The mechanism by which high levels of transferrin saturation interact with hepcidin expression is unclear. In particular, the question arises whether hepcidin is regulated in response to the serum transferrin saturation or whether decreased hepcidin expression is the primary event in HH associated with an increased transferrin saturation. In rats in which an acute-phase response was experimentally induced by injection of Freund complete adjuvant (FCA), hepcidin expression led to a decreased expression of intestinal iron transporters. Remarkably, hepcidin expression changed more rapidly than the expression of intestinal iron transporters and preceded the decline in transferrin saturation.39 This observation suggests that a change in hepcidin expression is a primary event in the acute-phase response and is in good agreement with the recent finding that hepcidin represents a type II acute-phase protein.37 However, the regulation of hepcidin expression under conditions of iron overload seems to be a complex process. In mice treated with iron-dextran, phenylhydrazine (PHZ)-induced acute hemolysis inhibits hepcidin expression despite iron overload.36 A similar phenomenon is seen in hypotransferrinemic hpx/hpx mice. In this murine model of hypotransferrinemia, hepcidin expression is decreased despite significant iron loading of the hepatocytes.33 Both conditions, acute hemolysis and hypotransferrinemia, are associated with nonphysiologic levels of NTBI.40-42 As high levels of NTBI are also found in individuals with a serum transferrin saturation above 80%,13,40,43 NTBI formation might explain why we did not find an up-regulation of hepcidin expression despite iron-overload in our patients with HH.

To analyze the interaction between NTBI and hepcidin expression, we incubated human hepatoma cells with increasing concentrations of Fe-NTA, a potent NTBI donor.40 In these cells, Fe-NTA concentrations as low as 10 µM induced a significant down-regulation of hepcidin mRNA expression. Interestingly, similar observations have been recently made in primary hepatocytes in which iron loading with 10 µM ferric ammonium citrate resulted in a 50% decrease in hepcidin mRNA.37 However, we could not demonstrate an effect of iron-saturated differic transferrin on hepcidin expression in our hepatoma cells.

These observations indicate that increasing levels of NTBI induce a down-regulation of hepcidin and, therefore, might explain the following phenomenon in iron metabolism: nonphysiologic levels of NTBI distinguish diseases such as hypotransferrinemia and atransferrinemia,41,42 thalassemia,44,45 and classical HH.13,43 These diseases are also characterized by intestinal hyperabsorption of iron and severe tissue iron overload. The exact mechanism leading to intestinal hyperabsorption in these clinically and pathogenetically different diseases is not yet clear. Most researchers favor the coexistence of a store and an erythropoietic regulator of iron homeostasis.2,11,12 The erythropoietic regulator might play a central role in the hyperabsorption of iron in hypotransferrinemia, a transferrinemia, and thalassemia, as these diseases are characterized by anemia.5,41,42 However, for the hypotransferrinemic hpx/hpx mice, it has been demonstrated that severe iron overload is not solely explained by anemia and the putative erythropoietic regulator. Transferrin levels influence iron absorption (especially mucosal transfer) independently of effects on hemoglobin levels.41 Thus, it might be speculated that impaired serum transferrin levels and the resulting formation of NTBI down-regulate hepatic hepcidin expression followed by an increase in intestinal iron absorption. This hypothesis is supported by recent findings in hypotransferrinemic hpx/hpx mice in which hepcidin is dramatically down-regulated despite significant iron loading of the hepatocytes,33 whereas the basolateral iron transporter IREG1 is up-regulated10 and, therefore, leads to an increased intestinal iron absorption.

As mentioned earlier, the inverse correlation between hepcidin expression and the serum transferrin saturation in our patients with HH might also result from the fact that hepcidin controls transferrin saturation. Therefore, an important question would be whether hepcidin expression influences the expression of additional genes that are involved in iron homeostasis and might, therefore, modify levels of serum transferrin saturation. These iron-related genes include TfR2, IREG1, DMT1-IRE, DMT1-nonIRE, and ceruloplasmin.2,11,12 In the present study, we analyzed whether the expression of hepcidin correlates with the expression of one of these genes. Interestingly, we found a strong correlation between expression of hepcidin and TfR2 in our liver biopsy samples, irrespective of the underlying disease or the iron status. The possible meaning of this correlation is unclear, as there is yet no evidence for a functional relationship between hepcidin and TfR2. However, it is noteworthy that mice with targeted mutations that abrogate expression of HFE,46,47 {beta}2m,48 TfR2,49 and hepcidin31 show almost the same phenotype with increased transferrin saturations, periportal hepatic iron loading, and reticuloendothelial iron sparing. Although these data suggest a close relationship between HFE/{beta}2m, TfR2, and hepcidin in the control of iron metabolism, the underlying mechanisms have to be further elucidated.

Taken together, the studies presented here would suggest that hepcidin appears to play different roles in iron homeostasis. The correlation between serum ferritin levels and hepatic hepcidin expression at normal levels of transferrin saturation is in good agreement with previous findings that have demonstrated an up-regulation of hepcidin in response to iron storage and the acute phase. In addition, hepcidin might act as a signaling molecule that modulates intestinal absorption in response to hemolysis, hypotransferrinemia, and high levels of serum transferrin saturation, apparently by a down-regulation of hepcidin expression in response to significant levels of NTBI. These interactions could play an important role in the pathogenesis of several iron-overload disorders, including thalassemia, hypotransferrinemia, a transferrinemia, and hemochromatosis. The recent finding that hepcidin is a type II acute-phase protein37 also implies a central role of this antimicrobial peptide in the anemia of chronic diseases.


   Footnotes
 
Submitted December 2, 2002; accepted February 27, 2003.

Prepublished online as Blood First Edition Paper, March 13, 2003; DOI 10.1182/blood-2002-11-3610.

Supported by grant STR 216/10-1 from the Deutsche Forschungsgemeinschaft and by the Dietmar Hopp Foundation.

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.

Reprints: Wolfgang Stremmel, University Hospital Heidelberg, Department of Internal Medicine IV, Bergheimer Strasse 58-69115, Heidelberg, Germany; e-mail: stremmel{at}medizin-online.com.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

  1. Adams PC. Iron overload in viral and alcoholic liver disease. J Hepatol. 1998;28(suppl 1): 19-20.[Medline] [Order article via Infotrieve]

  2. Andrews NC. Disorders of iron metabolism. N Engl J Med. 1999;341: 1986-1995.[Free Full Text]

  3. Bonkovsky HL, Lambrecht RW. Iron-induced liver injury. Clin Liver Dis. 2000;4: 409-429.[CrossRef][Medline] [Order article via Infotrieve]

  4. Boucher E, Bourienne A, Adams P, Turlin B, Brissot P, Deugnier Y. Liver iron concentration and distribution in chronic hepatitis C before and after interferon treatment. Gut. 1997;41: 115-120.[Abstract/Free Full Text]

  5. Angelucci E, Brittenham GM, McLaren CE, et al. Hepatic iron concentration and total iron burden iron stores in thalassemia major. N Engl J Med. 2000;343: 327-331.[Abstract/Free Full Text]

  6. Gunshin H, Mackenzie B, Berger UV, et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature. 1997;388: 482-488.[CrossRef][Medline] [Order article via Infotrieve]

  7. Fleming MD, Trenor CC, Su MA, et al. Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat Genet. 1997;16: 383-386.[CrossRef][Medline] [Order article via Infotrieve]

  8. Abboud S, Haile DJ. A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem. 2000;275: 19906-19912.[Abstract/Free Full Text]

  9. Donovan A, Brownlie A, Zhou Y, et al. Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature. 2000; 403: 776-781.[CrossRef][Medline] [Order article via Infotrieve]

  10. McKie AT, Marciani P, Rolfs A, et al. A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell. 2000;5: 299-309.[CrossRef][Medline] [Order article via Infotrieve]

  11. Roy CN, Enns CA. Iron homeostasis: new tales from the crypt. Blood. 2000;96: 4020-4027.[Abstract/Free Full Text]

  12. Philpott CC. Molecular aspects of iron absorption: insights into the role of HFE in hemochromatosis. Hepatology. 2002;35: 993-1001.[CrossRef]

  13. Loreal O, Gosriwatana I, Guyader D, Porter J, Brissot P, Hider RC. Determination of non-transferrin-bound iron in genetic hemochromatosis using a new HPLC-based method. J Hepatol. 2000;32: 727-733.[CrossRef][Medline] [Order article via Infotrieve]

  14. Kawabata H, Yang R, Hirama T, et al. Molecular cloning of transferrin receptor 2—a member of the transferrin receptor-like family. J Biol Chem. 1999;274: 20826-20832.[Abstract/Free Full Text]

  15. Fleming RE, Migas MC, Holden CC, et al. Transferrin receptor 2: continued expression in mouse liver in the face of iron overload and in hereditary hemochromatosis. Proc Natl Acad Sci U S A. 2000;97: 2214-2219.[Abstract/Free Full Text]

  16. Kawabata H, Germain RS, Ikezoe T, et al. Regulation of expression of murine transferrin receptor 2. Blood. 2001;98: 1949-1954.

  17. Feder JN, Gnirke A, Thomas W, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 1996; 13: 399-408.[CrossRef][Medline] [Order article via Infotrieve]

  18. Feder JN, Tsuchihashi Z, Irrinki A, et al. The hemochromatosis founder mutation in HLA-H disrupts {beta}2-microglobulin interaction and cell surface expression. J Biol Chem. 1997;272: 14025-14028.[Abstract/Free Full Text]

  19. Waheed A, Parkkila S, Zhou XY, et al. Hereditary hemochromatosis: effects of C282Y and H63D mutations on association with {beta}2-microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells. Proc Natl Acad Sci U S A. 1997;94: 12384-12389.[Abstract/Free Full Text]

  20. Feder JN, Penny DM, Irrinki A, et al. The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proc Natl Acad Sci U S A. 1998;95: 1472-1477.[Abstract/Free Full Text]

  21. Riedel HD, Muckenthaler MU, Gehrke SG, et al. HFE downregulates iron uptake from transferrin and induces iron-regulatory protein activity in stably transfected cells. Blood. 1999;94: 3915-3921.[Abstract/Free Full Text]

  22. Waheed A, Grubb JH, Zhou XY, et al. Regulation of transferrin-mediated iron uptake by HFE, the protein defective in hereditary hemochromatosis. Proc Natl Acad Sci U S A. 2002;99: 3117-3122.[Abstract/Free Full Text]

  23. Pietrangelo A. Physiology of iron transport and the hemochromatosis gene. Am J Physiol Gastrointest Liver Physiol. 2002;282: G403-G414.[Abstract/Free Full Text]

  24. Camaschella C, Roetto A, Cali A, et al. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet. 2000;25: 14-15.[CrossRef][Medline] [Order article via Infotrieve]

  25. Mattman A, Huntsman D, Lockitch G, et al. Transferrin receptor 2 (TfR2) and HFE mutational analysis in non-C282Y iron overload: identification of a novel TfR2 mutation. Blood. 2002;100: 1075-1077.[Abstract/Free Full Text]

  26. Montosi G, Donovan A, Totaro A, et al. Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest. 2001;108: 619-623.[CrossRef][Medline] [Order article via Infotrieve]

  27. Njajou OT, Vaessen N, Joosse M, et al. A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nat Genet. 2001;28: 213-214.[CrossRef][Medline] [Order article via Infotrieve]

  28. Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. 2001;276: 7806-7810.[Abstract/Free Full Text]

  29. Krause A, Neitz S, Mägert HJ, et al. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett. 2000; 480: 147-150.[CrossRef][Medline] [Order article via Infotrieve]

  30. Pigeon C, Ilyin G, Courselaud B, et al. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem. 2001;276: 7811-7819.[Abstract/Free Full Text]

  31. Nicolas G, Bennoun M, Devaux I, et al. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci U S A. 2001; 98: 8780-8785.[Abstract/Free Full Text]

  32. Nicolas G, Bennoun M, Porteu A, et al. Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. Proc Natl Acad Sci U S A. 2002;99: 4596-4601.[Abstract/Free Full Text]

  33. Weinstein DA, Roy CN, Fleming MD, Loda MF, Wolfsdorf JI, Andrews NC. Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease. Blood. 2002;100: 3776-3781.[Abstract/Free Full Text]

  34. Roetto A, Papanikolaou G, Politou M, et al. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet. 2003;33: 21-22.[CrossRef][Medline] [Order article via Infotrieve]

  35. Courseland B, Pigeon C, Inoue Y, et al. C/EBP{alpha} regulates hepatic transcription of hepcidin, an antimicrobial peptide and regulator of iron metabolism. J Biol Chem. 2002;277: 41163-41170.[Abstract/Free Full Text]

  36. Nicolas G, Chauvet C, Viatte L, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest. 2002;110: 1037-1044.[CrossRef][Medline] [Order article via Infotrieve]

  37. Nemeth E, Valore EV, Territo M, Schiller G, Lichtenstein A, Ganz T. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood. 2003;101: 2461-2463.[Abstract/Free Full Text]

  38. Frazer DM, Wilkins SJ, Becker EM, et al. Hepcidin expression inversely correlates with the expression of duodenal iron transporters and iron absorption in rats. Gastroenterology. 2002;123: 835-844.[CrossRef]

  39. Anderson GJ, Frazer DM, Wilkins SJ, et al. Relationship between intestinal iron-transporter expression, hepatic hepcidin levels and the control of iron absorption. Biochem Soc Trans. 2002;30: 724-726.[CrossRef][Medline] [Order article via Infotrieve]

  40. Von Bonsdorff L, Lindeberg E, Sahlstedt L, Lehto J, Parkkinen J. Bleomycin-detectable iron assay for non-transferrin-bound iron in hematologic malignancies. Clin Chem. 2002;48: 307-314.[Abstract/Free Full Text]

  41. Raja KB, Pountney DJ, Simpson RJ, Peters TJ. Importance of anemia and transferrin levels in the regulation of intestinal iron absorption in hypotransferrinemic mice. Blood. 1999;94: 3185-3192.[Abstract/Free Full Text]

  42. Beutler E, Gelbart T, Lee P, Trevino R, Fernandez MA, Fairbanks VF. Molecular characterization of a case of a transferrinemia. Blood. 2000;96: 4071-4074.[Abstract/Free Full Text]

  43. Breuer W, Cabantchik ZI. A fluorescence-based one-step assay for serum non-transferrin-bound iron. Anal Biochem. 2001;299: 194-202.[CrossRef][Medline] [Order article via Infotrieve]

  44. Al-Refaie FN, Wickens DG, Wonke B, Kontoghiorghes GJ, Hoffbrand AV. Serum non-transferrin-bound iron in beta-thalassaemia major patients treated with desferrioxamine and L1. Br J Haematol. 1992;82: 431-436.[Medline] [Order article via Infotrieve]

  45. Raja KB, Simpson RJ, Peters TJ. Intestinal iron absorption studies in mouse models of iron-overload. Br J Haematol. 1994;86: 156-162.[Medline] [Order article via Infotrieve]

  46. Zhou XY, Tomatsu S, Fleming RE, et al. HFE gene knockout produces mouse model of hereditary hemochromatosis. Proc Natl Acad Sci U S A. 1998;95: 2492-2497.[Abstract/Free Full Text]

  47. Levy JE, Montross LK, Cohen DE, Fleming MD, Andrews NC. The C282Y mutation causing hereditary hemochromatosis does not produce a null allele. Blood. 1999;94: 9-11.[Abstract/Free Full Text]

  48. Santos M, Schilham MW, Rademakers LH, Marx JJ, de Sousa M, Clevers H. Defective iron homeostasis in beta 2-microglobulin knockout mice recapitulates hereditary hemochromatosis in man. J Exp Med. 1996;184: 1975-1985.[Abstract/Free Full Text]

  49. Fleming RE, Ahmann JR, Migas MC, et al. Targeted mutagenesis of the murine transferrin receptor-2 gene produces hemochromatosis. Proc Natl Acad Sci U S A. 2002;99: 10653-10658.[Abstract/Free Full Text]


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 BloodHome page
P. Robach, S. Recalcati, D. Girelli, C. Gelfi, N. J. Aachmann-Andersen, J. J. Thomsen, A. M. Norgaard, A. Alberghini, N. Campostrini, A. Castagna, et al.
Alterations of systemic and muscle iron metabolism in human subjects treated with low-dose recombinant erythropoietin
Blood, June 25, 2009; 113(26): 6707 - 6715.
[Abstract] [Full Text] [PDF]

Home page
 haematolHome page
G. Ramey, J.-C. Deschemin, and S. Vaulont
Cross-talk between the mitogen activated protein kinase and bone morphogenetic protein/hemojuvelin pathways is required for the induction of hepcidin by holotransferrin in primary mouse hepatocytes
Haematologica, June 1, 2009; 94(6): 765 - 772.
[Abstract] [Full Text] [PDF]

Home page
 haematolHome page
M.-L. Island, A.-M. Jouanolle, A. Mosser, Y. Deugnier, V. David, P. Brissot, and O. Loreal
A new mutation in the hepcidin promoter impairs its BMP response and contributes to a severe phenotype in HFE related hemochromatosis
Haematologica, May 1, 2009; 94(5): 720 - 724.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
M. F Young, R. P Glahn, M. Ariza-Nieto, J. Inglis, G. Olbina, M. Westerman, and K. O O'Brien
Serum hepcidin is significantly associated with iron absorption from food and supplemental sources in healthy young women
Am. J. Clinical Nutrition, February 1, 2009; 89(2): 533 - 538.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
J. P. Pinto, S. Ribeiro, H. Pontes, S. Thowfeequ, D. Tosh, F. Carvalho, and G. Porto
Erythropoietin mediates hepcidin expression in hepatocytes through EPOR signaling and regulation of C/EBP{alpha}
Blood, June 15, 2008; 111(12): 5727 - 5733.
[Abstract] [Full Text] [PDF]

Home page
 J EndocrinolHome page
H. Kulaksiz, E. Fein, P. Redecker, W. Stremmel, G. Adler, and Y. Cetin
Pancreatic {beta}-cells express hepcidin, an iron-uptake regulatory peptide
J. Endocrinol., May 1, 2008; 197(2): 241 - 249.
[Abstract] [Full Text] [PDF]

Home page
 haematolHome page
E. Camberlein, G. Zanninelli, L. Detivaud, A. R. Lizzi, F. Sorrentino, S. Vacquer, M.-B. Troadec, E. Angelucci, E. Abgueguen, O. Loreal, et al.
Anemia in -thalassemia patients targets hepatic hepcidin transcript levels independently of iron metabolism genes controlling hepcidin expression
Haematologica, January 1, 2008; 93(1): 111 - 115.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
A. Piperno, D. Girelli, E. Nemeth, P. Trombini, C. Bozzini, E. Poggiali, Y. Phung, T. Ganz, and C. Camaschella
Blunted hepcidin response to oral iron challenge in HFE-related hemochromatosis
Blood, December 1, 2007; 110(12): 4096 - 4100.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
L. Lin, E. V. Valore, E. Nemeth, J. B. Goodnough, V. Gabayan, and T. Ganz
Iron transferrin regulates hepcidin synthesis in primary hepatocyte culture through hemojuvelin and BMP2/4
Blood, September 15, 2007; 110(6): 2182 - 2189.
[Abstract] [Full Text] [PDF]

Home page
 GutHome page
C. Hutchinson, C. A Geissler, J. J Powell, and A. Bomford
Proton pump inhibitors suppress absorption of dietary non-haem iron in hereditary haemochromatosis
Gut, September 1, 2007; 56(9): 1291 - 1295.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
U. Merle, E. Fein, S. G. Gehrke, W. Stremmel, and H. Kulaksiz
The Iron Regulatory Peptide Hepcidin Is Expressed in the Heart and Regulated by Hypoxia and Inflammation
Endocrinology, June 1, 2007; 148(6): 2663 - 2668.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
T. Ganz
Molecular Control of Iron Transport
J. Am. Soc. Nephrol., February 1, 2007; 18(2): 394 - 400.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
O. Olakanmi, L. S. Schlesinger, and B. E. Britigan
Hereditary hemochromatosis results in decreased iron acquisition and growth by Mycobacterium tuberculosis within human macrophages
J. Leukoc. Biol., January 1, 2007; 81(1): 195 - 204.
[Abstract] [Full Text] [PDF]

Home page
 J. Cell Sci.Home page
A. Calzolari, C. Raggi, S. Deaglio, N. M. Sposi, M. Stafsnes, K. Fecchi, I. Parolini, F. Malavasi, C. Peschle, M. Sargiacomo, et al.
TfR2 localizes in lipid raft domains and is released in exosomes to activate signal transduction along the MAPK pathway
J. Cell Sci., November 1, 2006; 119(21): 4486 - 4498.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
N.-B. Nguyen, K. D. Callaghan, A. J. Ghio, D. J. Haile, and F. Yang
Hepcidin expression and iron transport in alveolar macrophages
Am J Physiol Lung Cell Mol Physiol, September 1, 2006; 291(3): L417 - L425.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
K. B Hadley, L. K Johnson, and J. R Hunt
Iron absorption by healthy women is not associated with either serum or urinary prohepcidin
Am. J. Clinical Nutrition, July 1, 2006; 84(1): 150 - 155.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Chem.Home page
D. W. Swinkels, M. C.H. Janssen, J. Bergmans, and J. J.M. Marx
Hereditary Hemochromatosis: Genetic Complexity and New Diagnostic Approaches
Clin. Chem., June 1, 2006; 52(6): 950 - 968.
[Abstract] [Full Text] [PDF]

Home page
 GutHome page
A Pietrangelo
Molecular insights into the pathogenesis of hereditary haemochromatosis.
Gut, April 1, 2006; 55(4): 564 - 568.
[Full Text] [PDF]

Home page
 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
T. Ganz and E. Nemeth
Iron imports. IV. Hepcidin and regulation of body iron metabolism
Am J Physiol Gastrointest Liver Physiol, February 1, 2006; 290(2): G199 - G203.
[Abstract] [Full Text] [PDF]

Home page
 ASH Education BookHome page
P. Brissot and F. de Bels
Current Approaches to the Management of Hemochromatosis
Hematology, January 1, 2006; 2006(1): 36 - 41.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
C. Camaschella
Understanding iron homeostasis through genetic analysis of hemochromatosis and related disorders
Blood, December 1, 2005; 106(12): 3710 - 3717.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
L. Detivaud, E. Nemeth, K. Boudjema, B. Turlin, M.-B. Troadec, P. Leroyer, M. Ropert, S. Jacquelinet, B. Courselaud, T. Ganz, et al.
Hepcidin levels in humans are correlated with hepatic iron stores, hemoglobin levels, and hepatic function
Blood, July 15, 2005; 106(2): 746 - 748.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
J. F. Collins, C. A. Franck, K. V. Kowdley, and F. K. Ghishan
Identification of differentially expressed genes in response to dietary iron deprivation in rat duodenum
Am J Physiol Gastrointest Liver Physiol, May 1, 2005; 288(5): G964 - G971.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
E. Nemeth, A. Roetto, G. Garozzo, T. Ganz, and C. Camaschella
Hepcidin is decreased in TFR2 hemochromatosis
Blood, February 15, 2005; 105(4): 1803 - 1806.
[Abstract] [Full Text] [PDF]

Home page
 J EndocrinolHome page
H Kulaksiz, F Theilig, S Bachmann, S G Gehrke, D Rost, A Janetzko, Y Cetin, and W Stremmel
The iron-regulatory peptide hormone hepcidin: expression and cellular localization in the mammalian kidney
J. Endocrinol., February 1, 2005; 184(2): 361 - 370.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
H. Kawabata, R. E. Fleming, D. Gui, S. Y. Moon, T. Saitoh, J. O'Kelly, Y. Umehara, Y. Wano, J. W. Said, and H. P. Koeffler
Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis
Blood, January 1, 2005; 105(1): 376 - 381.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
M. B. Johnson and C. A. Enns
Diferric transferrin regulates transferrin receptor 2 protein stability
Blood, December 15, 2004; 104(13): 4287 - 4293.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
A. Robb and M. Wessling-Resnick
Regulation of transferrin receptor 2 protein levels by transferrin
Blood, December 15, 2004; 104(13): 4294 - 4299.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Cell Physiol.Home page
A. D. Robb, M. Ericsson, and M. Wessling-Resnick
Transferrin receptor 2 mediates a biphasic pattern of transferrin uptake associated with ligand delivery to multivesicular bodies
Am J Physiol Cell Physiol, December 1, 2004; 287(6): C1769 - C1775.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
P. Lee, H. Peng, T. Gelbart, and E. Beutler
The IL-6- and lipopolysaccharide-induced transcription of hepcidin in HFE-, transferrin receptor 2-, and {beta}2-microglobulin-deficient hepatocytes
PNAS, June 22, 2004; 101(25): 9263 - 9265.
[Abstract] [Full Text] [PDF]

Home page
 NEJMHome page
A. Pietrangelo
Hereditary Hemochromatosis -- A New Look at an Old Disease
N. Engl. J. Med., June 3, 2004; 350(23): 2383 - 2397.
[Full Text] [PDF]

Home page
 BloodHome page
C. Lanzara, A. Roetto, F. Daraio, S. Rivard, R. Ficarella, H. Simard, T. M. Cox, M. Cazzola, A. Piperno, A.-P. Gimenez-Roqueplo, et al.
Spectrum of hemojuvelin gene mutations in 1q-linked juvenile hemochromatosis
Blood, June 1, 2004; 103(11): 4317 - 4321.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. GenomicsHome page
D. Barisani, A. Parafioriti, M. T. Bardella, H. Zoller, D. Conte, E. Armiraglio, C. Trovato, R. O. Koch, and G. Weiss
Adaptive changes of duodenal iron transport proteins in celiac disease
Physiol Genomics, May 19, 2004; 17(3): 316 - 325.
[Abstract] [Full Text] [PDF]

Home page
 GutHome page
K J Robson
Hepcidin and its role in iron absorption
Gut, May 1, 2004; 53(5): 617 - 619.
[Abstract] [Full Text] [PDF]

Home page
 GutHome page
H Kulaksiz, S G Gehrke, A Janetzko, D Rost, T Bruckner, B Kallinowski, and W Stremmel
Pro-hepcidin: expression and cell specific localisation in the liver and its regulation in hereditary haemochromatosis, chronic renal insufficiency, and renal anaemia
Gut, May 1, 2004; 53(5): 735 - 743.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
D.-Q. Lou, G. Nicolas, J.-C. Lesbordes, L. Viatte, G. Grimber, M.-F. Szajnert, A. Kahn, and S. Vaulont
Functional differences between hepcidin 1 and 2 in transgenic mice
Blood, April 1, 2004; 103(7): 2816 - 2821.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
A. Roetto, F. Daraio, P. Porporato, R. Caruso, T. M. Cox, M. Cazzola, P. Gasparini, A. Piperno, and C. Camaschella
Screening hepcidin for mutations in juvenile hemochromatosis: identification of a new mutation (C70R)
Blood, March 15, 2004; 103(6): 2407 - 2409.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
A.-S. Zhang, S. Xiong, H. Tsukamoto, and C. A. Enns
Localization of iron metabolism-related mRNAs in rat liver indicate that HFE is expressed predominantly in hepatocytes
Blood, February 15, 2004; 103(4): 1509 - 1514.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Chem.Home page
C. Brugnara
Iron Deficiency and Erythropoiesis: New Diagnostic Approaches
Clin. Chem., October 1, 2003; 49(10): 1573 - 1578.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
2002-11-3610v1
102/1/371    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Right arrow Rights and Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gehrke, S. G.
Right arrow Articles by Stremmel, W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gehrke, S. G.
Right arrow Articles by Stremmel, W.
Related Collections
Right arrow Red Cells
Right arrow Gene Expression
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

click for free articles
home about blood authors subscriptions permissions advertising public access contact us
  Copyright © 2003 by American Society of Hematology         Online ISSN: 1528-0020