Concept: Iron metabolism
There is increasing evidence from clinical and population studies for a role of H. pylori infection in the aetiology of iron deficiency. Rodent models of Helicobacter infection are helpful for investigating any causal links and mechanisms of iron deficiency in the host. The aim of this study was to investigate the effects of gastric Helicobacter infection on iron deficiency and host iron metabolism/transport gene expression in hypergastrinemic INS-GAS mice. INS-GAS mice were infected with Helicobacter felis for 3, 6 and 9 months. At post mortem, blood was taken for assessment of iron status and gastric mucosa for pathology, immunohistology and analysis of gene expression. Chronic Helicobacter infection of INS- GAS mice resulted in decreased serum iron, transferrin saturation and hypoferritinemia and increased Total iron binding capacity (TIBC). Decreased serum iron concentrations were associated with a concomitant reduction in the number of parietal cells, strengthening the association between hypochlorhydria and gastric Helicobacter-induced iron deficiency. Infection with H. felis for nine months was associated with decreased gastric expression of iron metabolism regulators hepcidin, Bmp4 and Bmp6 but increased expression of Ferroportin 1, the iron efflux protein, iron absorption genes such as Divalent metal transporter 1, Transferrin receptor 1 and also Lcn2 a siderophore-binding protein. The INS-GAS mouse is therefore a useful model for studying Helicobacter-induced iron deficiency. Furthermore, the marked changes in expression of gastric iron transporters following Helicobacter infection may be relevant to the more rapid development of carcinogenesis in the Helicobacter infected INS-GAS model.
- Tidsskrift for den Norske lægeforening : tidsskrift for praktisk medicin, ny række
- Published about 6 years ago
BACKGROUND Iron deficiency and iron deficiency anaemia are frequent problems in both the primary and the specialist health services. It is important to detect iron deficiency and to determine the causal relationship because iron deficiency may be secondary to a serious disease. The diagnosis of iron deficiency is largely based on biochemical and haematological laboratory findings, but there is no standardisation or consensus on the interpretation of these findings.METHOD Non-systematic search in the PubMed database with a discretionary selection of articles, based on the authors' knowledge of the field.RESULTS Ferritin measurement is the most important analysis in the study of iron deficiency, but there is no consensus on the diagnostic cut-off. It is usual in Norway today to use a ferritin level of < 12 - 20 μg/L, but at this low level the sensitivity for detecting iron deficiency is very low. A number of studies show that if the diagnostic cut-off is increased to the order of 30 μg/L the sensitivity is significantly higher for only a small reduction in specificity.INTERPRETATION When studying iron deficiency as a cause of anaemia, the diagnostic cut-off for detecting deficiency should be higher than that used today. The ferritin level increases with inflammation and ought in practice to be considered in conjunction with the CRP level. The level of transferrin receptor in plasma increases with iron deficiency without being influenced by inflammation and is therefore a good supplement to ferritin measurement. Measurement of iron, transferrin and transferrin saturation provides little information additional to that provided by ferritin in iron deficiency studies.
The iron regulatory hormone hepcidin responds to both oral and parenteral iron. Here, we hypothesized that the diverse iron trafficking routes may affect the dynamics and kinetics of the hepcidin activation pathway. To address this, C57BL/6 mice were administered an iron-enriched diet or injected i.p. with iron dextran and analyzed over time. After 1 week of dietary loading with carbonyl iron, mice exhibited significant increases in serum iron and transferrin saturation, as well as in hepatic iron, Smad1/5/8 phosphorylation and bone morphogenetic protein 6 (BMP6), and hepcidin mRNAs. Nevertheless, hepcidin expression reached a plateau afterward, possibly due to upregulation of inhibitory Smad7, Id1, and matriptase-2 mRNAs, while hepatic and splenic iron continued to accumulate over 9 weeks. One day following parenteral administration of iron dextran, mice manifested elevated serum and hepatic iron levels and Smad1/5/8 phosphorylation, but no increases in transferrin saturation or BMP6 mRNA. Surprisingly, hepcidin failed to appropriately respond to acute overload with iron dextran, and a delayed (after 5-7 days) hepcidin upregulation correlated with increased transferrin saturation, partial relocation of iron from macrophages to hepatocytes, and induction of BMP6 mRNA. Our data suggest that the physiological hepcidin response is saturable and are consistent with the idea that hepcidin senses exclusively iron compartmentalized within circulating transferrin and/or hepatocytes.
Ferroportin exports iron into plasma from absorptive enterocytes, erythrophagocytosing macrophages, and hepatic stores. The hormone hepcidin controls cellular iron export and plasma iron concentrations by binding to ferroportin and causing its internalization and degradation. We explored the mechanism of hepcidin-induced endocytosis of ferroportin, the key molecular event in systemic iron homeostasis. Hepcidin binding caused rapid ubiquitination of ferroportin in cell lines overexpressing ferroportin and in murine bone marrow-derived macrophages. No hepcidin-dependent ubiquitination was observed in C326S ferroportin mutant which does not bind hepcidin. Substitutions of lysines between residues 229 and 269 in the third cytoplasmic loop of ferroportin prevented hepcidin-dependent ubiquitination and endocytosis of ferroportin, and promoted cellular iron export even in the presence of hepcidin. The human ferroportin mutation K240E, previously associated with clinical iron overload, caused hepcidin resistance in vitro by interfering with ferroportin ubiquitination. Our study demonstrates that ubiquitination is the functionally relevant signal for hepcidin-induced ferroportin endocytosis.
Serum Hepcidin Is Associated With Presence of Plaque in Postmenopausal Women of a General Population
- Arteriosclerosis, thrombosis, and vascular biology
- Published over 5 years ago
Iron and the iron regulatory hormone hepcidin, major determinant of body iron distribution, are hypothesized to play a role in cardiovascular disease. Here, we assess the associations of hepcidin as well as ferritin, iron, total iron-binding capacity, and transferrin saturation (ie, iron parameters) with noninvasive measurements of atherosclerosis in men and women of a population-based cohort.
The transferrin receptor (TfR1), which mediates cellular iron uptake through clathrin-dependent endocytosis of iron-loaded transferrin, plays a key role in iron homeostasis. Since the number of TfR1 molecules at the cell surface is the rate-limiting step for iron entry into cells and is essential to prevent iron overload, TfR1 expression is precisely controlled at multiple levels. In this review, we have discussed the latest advances in the molecular regulation of TfR1 expression and we have considered current understanding of TfR1 function beyond its canonical role in providing iron for erythroid precursors and rapidly proliferating cells.
Hereditary hemochromatosis (HH) is a common autosomal-recessive disorder associated with pathogenic HFE variants, most commonly those resulting in p.Cys282Tyr and p.His63Asp. Recommendations on returning incidental findings of HFE variants in individuals undergoing genome-scale sequencing should be informed by penetrance estimates of HH in unselected samples. We used the eMERGE Network, a multicenter cohort with genotype data linked to electronic medical records, to estimate the diagnostic rate and clinical penetrance of HH in 98 individuals homozygous for the variant coding for HFE p.Cys282Tyr and 397 compound heterozygotes with variants resulting in p.[His63Asp];[Cys282Tyr]. The diagnostic rate of HH in males was 24.4% for p.Cys282Tyr homozygotes and 3.5% for compound heterozygotes (p < 0.001); in females, it was 14.0% for p.Cys282Tyr homozygotes and 2.3% for compound heterozygotes (p < 0.001). Only males showed differences across genotypes in transferrin saturation levels (100% of homozygotes versus 37.5% of compound heterozygotes with transferrin saturation > 50%; p = 0.003), serum ferritin levels (77.8% versus 33.3% with serum ferritin > 300 ng/ml; p = 0.006), and diabetes (44.7% versus 28.0%; p = 0.03). No differences were found in the prevalence of heart disease, arthritis, or liver disease, except for the rate of liver biopsy (10.9% versus 1.8% [p = 0.013] in males; 9.1% versus 2% [p = 0.035] in females). Given the higher rate of HH diagnosis than in prior studies, the high penetrance of iron overload, and the frequency of at-risk genotypes, in addition to other suggested actionable adult-onset genetic conditions, opportunistic screening should be considered for p.[Cys282Tyr];[Cys282Tyr] individuals with existing genomic data.
Regulation of iron metabolism and innate immunity are tightly interlinked. The acute phase response to infection and inflammation induces alterations in iron homeostasis that reduce iron supplies to pathogens. The iron-hormone hepcidin is activated by such stimuli causing degradation of the iron exporter ferroportin and reduced iron release from macrophages, suggesting that hepcidin is the crucial effector of inflammatory hypoferremia. Here we report the discovery of an acute inflammatory condition that is mediated by Toll-like receptor (TLR) 2 and TLR6 and which induces hypoferremia in mice injected with TLR ligands. Stimulation of TLR2/TLR6 triggers profound decreases in ferroportin mRNA and protein expression in bone marrow-derived macrophages, liver and spleen of mice without changing hepcidin expression. Furthermore, C326S ferroportin mutant mice with a disrupted hepcidin/ferroportin regulatory circuitry respond to injection of the TLR2/6 ligands FSL1 or PAM3CSK4 by ferroportin down regulation and a reduction of serum iron levels. Our findings challenge the prevailing role of hepcidin in hypoferremia and suggest that rapid hepcidin-independent ferroportin down regulation in the major sites of iron recycling may represent a first line response to restrict iron access for numerous pathogens.
Iron metabolism is regulated by transcriptional and post-transcriptional mechanisms. The mRNA of the iron-controlling gene, transferrin receptor 1 (TfR1), has long been believed to be negatively regulated by a yet-unidentified endonuclease. Here, we show that the endonuclease Regnase-1 is critical for the degradation of mRNAs involved in iron metabolism in vivo. First, we demonstrate that Regnase-1 promotes TfR1 mRNA decay. Next, we show that Regnase-1(-/-) mice suffer from severe iron deficiency anemia, although hepcidin expression is downregulated. The iron deficiency anemia is induced by a defect in duodenal iron uptake. We reveal that duodenal Regnase-1 controls the expression of PHD3, which impairs duodenal iron uptake via HIF2α suppression. Finally, we show that Regnase-1 is a HIF2α-inducible gene and thus provides a positive feedback loop for HIF2α activation via PHD3. Collectively, these results demonstrate that Regnase-1-mediated regulation of iron-related transcripts is essential for the maintenance of iron homeostasis.
Both iron overload and iron deficiency have been associated with cardiomyopathy and heart failure, but cardiac iron utilization is incompletely understood. We hypothesized that the transferrin receptor (Tfr1) might play a role in cardiac iron uptake and used gene targeting to examine the role of Tfr1 in vivo. Surprisingly, we found that decreased iron, due to inactivation of Tfr1, was associated with severe cardiac consequences. Mice lacking Tfr1 in the heart died in the second week of life and had cardiomegaly, poor cardiac function, failure of mitochondrial respiration, and ineffective mitophagy. The phenotype could only be rescued by aggressive iron therapy, but it was ameliorated by administration of nicotinamide riboside, an NAD precursor. Our findings underscore the importance of both Tfr1 and iron in the heart, and may inform therapy for patients with heart failure.