Dietary iron loading does not influence biliary iron excretion in rats

1992 ◽  
Vol 35 (1) ◽  
pp. 73-75 ◽  
Author(s):  
Shiguang Yu ◽  
Anton C. Beynen
Keyword(s):  
Dietary Iron ◽  
Iron Loading ◽  
Iron Excretion

Comparison of cytosolic products formed in rat liver in response to parenteral and dietary iron loading

1992 ◽  
Vol 35 (1) ◽  
pp. 47-54 ◽  
Author(s):  
P. L. Ringeling ◽  
M. I. Cleton ◽  
M. I. E. Huijskes-Heins ◽  
W. C. de Bruijn ◽  
H. G. van Eijk
Keyword(s):  
Rat Liver ◽  
Dietary Iron ◽  
Iron Loading

scholarly journals Effect of Dietary Iron Loading on Recognition Memory in Growing Rats

PLoS ONE ◽  
2015 ◽  
Vol 10 (3) ◽  
pp. e0120609 ◽  
Author(s):  
Murui Han ◽  
Jonghan Kim
Keyword(s):  
Recognition Memory ◽  
Dietary Iron ◽  
Iron Loading ◽  
Growing Rats

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.

Intensive Iron-Chelation Therapy with Desferrioxamine in Iron-Loading Anaemias

1978 ◽  
Vol 54 (1) ◽  
pp. 99-106 ◽  
Author(s):  
M. J. Pippard ◽  
S. T. Callender ◽  
D. J. Weatherall
Keyword(s):  
Chelation Therapy ◽  
Iron Chelation ◽  
Mean Value ◽  
Linear Increase ◽  
Total Iron ◽  
Iron Loading ◽  
Iron Load ◽  
Excretion Rates ◽  
Kinetics Of ◽  
Iron Excretion

1. Urinary iron excretion after desferrioxamine has been examined in nine patients with different iron-loading anaemias. Particular attention has been paid to individual variation in response and the kinetics of iron removal in order to determine the most efficient and convenient method of administration. 2. Twelve-hour subcutaneous infusions of desferrioxamine were comparable with intravenous infusions and gave a mean value of 62% more iron excretion than similar intramuscular bolus doses (range 20–125%). 3. Increasing doses as 12 h subcutaneous infusions produced a linear increase in iron excretion, which was followed by a tendency to reach a plateau. Iron excretion varied greatly between patients, was not related solely to age or estimated iron load, and in most cases was increased by ascorbic acid saturation. 4. Maximum iron-excretion rates were achieved after 3–6 h and then maintained throughout an infusion. With bolus injections excretion rates declined rapidly after the first 6 h, during which approximately 60% of the total iron excretion occurred. 5. The dose and method of administration should be ‘tailor-made’ for each patient. Overnight 12 h subcutaneous infusions can be both as effective as similar doses given over 24 h and a practical way of achieving substantial negative iron balance. 6. Since children receiving regular blood transfusions for congenital anaemias such as thalassaemia usually die at the end of the second decade, this approach to iron chelation offers the possibility of alleviating what have hitherto been fatal iron-loading states.

Tissue-Specific Regulation of Iron Release in Response to Body Iron Status Under Erythropoietic Stimulation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2148-2148
Author(s):  
Yukari Matsuo-Tezuka ◽  
Mariko Noguchi-Sasaki ◽  
Mitsue Kurasawa ◽  
Keigo Yorozu ◽  
Yasushi Shimonaka
Keyword(s):  
Mass Spectrometry ◽  
Iron Status ◽  
Treated Group ◽  
Dietary Iron ◽  
Iron Loading ◽  
Hemoglobin Synthesis ◽  
Expression Levels ◽  
Body Iron ◽  
Natural Iron ◽  
Serum Hepcidin

Abstract Introduction: In a previous study, we demonstrated that dietary iron uptake and mobilization of stored iron are both up-regulated through suppression of serum hepcidin levels during erythropoietic stimulation by administration of Epoetin beta pegol (C.E.R.A.), a long-acting erythropoiesis-stimulating agent. It was also demonstrated that up-regulation of ferroportin (FPN) in reticuloendothelial macrophages and up-regulation of divalent metal transporter 1 (DMT1) and FPN in enterocytes are followed by hepcidin suppression; however, the quantitative contribution of dietary iron for erythropoiesis were undetermined. In this study, we investigated how utilization of dietary iron for erythropoiesis is regulated under erythropoietic stimulation by C.E.R.A. in mice with different body iron status. To quantitatively estimate utilization of dietary iron for hemoglobin synthesis, we used a dietary iron tracing method using the stable iron isotope 57Fe. Methods: To assess dietary iron-derived hemoglobin synthesis, a diet containing 200 ppm of 57Fe instead of natural iron (57Fe-diet) was used. A diet containing 200 ppm of natural iron (native Fe diet) was used as a control. C57BL/6NCrl mice were fed the native Fe diet and were intravenously administered 0.5 or 1.0 mg/mouse of iron dextran (iron-loaded condition) or dextran (control). Five days after iron loading, the diet was switched to the 57Fe-diet immediately after intravenous injection of 10 µg/kg of C.E.R.A. or vehicle. On Day 5 and 8 after C.E.R.A. treatment, mice were euthanized by exsanguination under anesthesia with isoflurane, and hemoglobin levels were measured. Expression levels of DMT1 and FPN in control and iron-loaded mice (1.0 mg/mouse) on Day 5 were estimated by immunohistochemistry. Serum hepcidin levels on Day 5 were also measured by liquid column chromatography-tandem mass spectrometry (LC-MS/MS). To quantify dietary iron-derived hemoglobin synthesis, the content of hemoglobin containing 57Fe (57Fe-hemoglobin) was measured on Day 8 by inductively coupled plasma mass spectrometry (ICP-MS). Results: Hemoglobin levels on Day 8 were significantly higher in the C.E.R.A.-treated groups than in the vehicle-treated groups for each iron conditions. In the C.E.R.A.-treated groups, although iron loading did not affect hemoglobin levels, 57Fe-hemoglobin levels were significantly decreased with iron loading. The serum hepcidin levels were significantly suppressed in each of the C.E.R.A.-treated groups. However, iron loading increased serum hepcidin levels on Day 5 in both the vehicle- and C.E.R.A.-treated groups. The expression levels of hepatic and splenic iron exporter FPN were not significantly changed by iron loading in the C.E.R.A.-treated group. In contrast, the expression levels of intestinal iron transporters DMT1 and FPN were significantly reduced by iron loading in the C.E.R.A.-treated group. Conclusion: Iron loading reduced utilization of dietary iron for hemoglobin synthesis under erythropoietic stimulation by C.E.R.A. treatment. However, iron loading did not affect total hemoglobin levels, indicating that the contribution of dietary iron and stored iron for erythropoiesis is properly controlled in response to body iron status. This was attributed to the tissue-specific regulatory mechanisms of iron transporters in iron absorptive tissue (intestine) and iron storage tissue (liver and spleen) in response to iron loading even FPN on both tissues is known to be commonly down-regulated by hepcidin-binding. Sensitive inactivation of iron importers and exporters in the duodenum under conditions of iron loading may effectively contribute to iron not being excessively incorporated under erythropoietic stimulation. Disclosures Noguchi-Sasaki: Chugai Pharmaceutical Co., Ltd.: Employment. Kurasawa:Chugai Pharmaceutical Co., Ltd.: Employment. Yorozu:Chugai Pharmaceutical Co., Ltd.: Employment. Shimonaka:Chugai Pharmaceutical Co., Ltd.: Employment.

scholarly journals Consumption of a high-iron diet disrupts homeostatic regulation of intestinal copper absorption in adolescent mice

2017 ◽  
Vol 313 (4) ◽  
pp. G353-G360 ◽  
Author(s):  
Jung-Heun Ha ◽  
Caglar Doguer ◽  
James F. Collins
Keyword(s):  
Iron Overload ◽  
Copper Deficiency ◽  
Copper Homeostasis ◽  
Dietary Iron ◽  
Iron Loading ◽  
Homeostatic Regulation ◽  
Dietary Copper ◽  
Copper Absorption ◽  
High Iron ◽  
Copper Depletion

High-iron feeding of rodents has been commonly used to model human iron-overload disorders. We recently noted that high-iron consumption impaired growth and caused severe systemic copper deficiency in growing rats, but the mechanism by which this occurred could not be determined due to technical limitations. In the current investigation, we thus utilized mice; first to determine if the same phenomenon occurred in another mammalian species, and second since we could assess in vivo copper absorption in mice. We hypothesized that excessive dietary iron impaired intestinal copper absorption. Weanling, male mice were thus fed AIN-93G-based diets containing high (HFe) (~8,800 ppm) or adequate (AdFe) (~80 ppm) iron in combination with low (~0.9 ppm), adequate (~9 ppm), or high (~180 ppm) copper for several weeks. Iron and copper homeostasis was subsequently assessed. Mice consuming the HFe diets grew slower, were anemic, and had lower hepatic copper levels and serum ceruloplasmin activity. These physiological perturbations were all prevented by higher dietary copper, demonstrating that copper depletion was the underlying cause. Furthermore, homeostatic regulation of copper absorption was noted in the mice consuming the AdFe diets, with absorption increasing as dietary copper decreased. HFe-fed mice did not have impaired copper absorption (disproving our hypothesis), but homeostatic control of absorption was disrupted. There were also noted perturbations in the tissue distribution of copper in the HFe-fed mice, suggesting that altered storage and thus bioavailability contributed to the noted copper deficiency. Dietary iron loading thus antagonizes copper homeostasis leading to pathological symptoms of severe copper depletion. NEW & NOTEWORTHY High-iron feeding is a common experimental method to model human iron-overload disorders in rodents. Here, we show that dietary iron loading causes severe copper deficiency due to perturbations in the homeostatic regulation of intestinal copper absorption and tissue distribution, which may decrease the bioavailability of copper for use in cuproenzyme synthesis. Whether high-dose iron supplementation in humans antagonizes copper homeostasis is worthy of consideration.

Inactivating Hfe Totally Abolishes Hepcidin Production and Further Aggravates Iron Overload In Bmp6-Deficient Mice

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 178-178
Author(s):  
Chloe Latour ◽  
Celine Besson-Fournier ◽  
Nelly Rouquie ◽  
Léon Kautz ◽  
Patricia Aguilar-Martinez ◽  
...  
Keyword(s):  
Iron Overload ◽  
Hepatic Iron ◽  
Dietary Iron ◽  
Iron Loading ◽  
Wild Type ◽  
Severe Phenotype ◽  
Double Knockout ◽  
Hepcidin Expression ◽  
Hepatic Iron Overload

Abstract Hepcidin, a circulating hormone produced primarily by the liver, plays a central role in the regulation of systemic iron homeostasis necessary to ensure sufficient availability of iron for hemoglobin synthesis and other metabolic processes while avoiding the oxidative damage to cells that can result from excess free iron. Hepcidin triggers internalization and degradation of ferroportin, the only known iron export channel from cells into the plasma, which leads to the decrease of dietary iron absorption from duodenal enterocytes and to the sequestration of iron recycled from senescent blood cells within macrophages. Iron overload induces the expression of bone morphogenetic protein 6 (BMP6), a member of the TGF-beta superfamily of ligands, which activates a signaling cascade leading to SMAD1/5/8 phosphorylation, translocation of the phosphorylated SMADs bound to SMAD4 to the nucleus, and upregulation of hepcidin gene transcription. Inactivation of Bmp6 in mice leads to considerably reduced hepcidin production, compared with wild-type mice, and severe hepatic iron overload. However, there are major differences in hepcidin expression and extrahepatic tissue iron loading between Bmp6-deficient males and females, due to the suppressive effect of testosterone on hepcidin in males. In contrast to males, Bmp6-/- females still produce some hepcidin and do not massively accumulate iron in their pancreas, their heart or their kidneys. The goal of this study was to investigate the role of Hfe in the residual hepcidin production observed in the absence of Bmp6 in females. Mutations in the HFE gene are causing the most common form of hereditary hemochromatosis, a disorder characterized by a chronic inappropriate increase in dietary iron uptake, progressive iron overload and tissue injury. Human patients and mouse models of HFE-related hemochromatosis show inappropriately low expression of hepcidin. However, the mechanism by which HFE influences hepcidin expression is still unclear. In Hfe-/- mice and in patients with HFE-associated hemochromatosis, the induction of BMP6 mRNA by iron is intact, but hepcidin production is impaired. In the mouse, Hfe and Bmp6 genes are separated by less than 8 cM on chromosome 13, and the probability of obtaining recombinants between the 2 loci is low. However, HFE is a non-classical MHC class 1-like molecule which associates with β2-microglobulin and β2m-/- mice develop spontaneously hepatic iron overload with a distribution similar to that seen in the liver of Hfe-/- mice. We therefore generated β2m/Bmp6 double knockout mice in which the function of both Hfe and Bmp6 is impaired. Briefly, Bmp6-/- mice on a CD1 background were mated to β2m-/- mice on a C57BL/6 background and double heterozygote F1 mice were intercrossed. We assessed Smad1/5/8 phosphorylation, hepcidin expression, and the sites of iron accumulation in wild-type, simple knockout (β2m-/- or Bmp6-/-) and double knockout (β2m-/- and Bmp6-/-) mice of the F2 progeny. Interestingly, the lack of functional Hfe in Bmp6-/- females led to a much more severe phenotype than the single impairment of Bmp6, with massive iron loading in extrahepatic tissues, most notably the exocrine pancreas, the heart, and the proximal and distal convoluted tubules of the kidney. Phosphorylation of Smad1/5/8 in double knockout (β2m-/- and Bmp6-/-) mice was virtually abolished and hepcidin mRNA in double knockout females was much more strongly downregulated than in single Bmp6-/- females. In contrast to Bmp6-/- females, no protein was detectable by ELISA in double knockout mice. Our findings show that Bmp6 and Hfe regulate hepcidin production by two independent pathways that converge on Smad1/5/8 phosphorylation. The role of transferrin receptor 2 (TFR2), another hemochromatosis-associated molecule, remains a key question. The total suppression of hepcidin in mice in which both Hfe and Bmp6 have been impaired suggests that TFR2 does not regulate hepcidin through an additional pathway. Moreover, the observation that Hfe-/-/Tfr2-/- mice have a more severe phenotype than simple Hfe-/- or Tfr2-/- mice favors the interference of Tfr2 with the Bmp6 pathway. Comparison of the phenotype of mice with inactivation of both Bmp6 and Tfr2 to that of Bmp6-/- mice is likely to definitively solve this still open question. Disclosures: No relevant conflicts of interest to declare.

Altered dietary iron intake is a strong modulator of renal DMT1 expression

2003 ◽  
Vol 285 (6) ◽  
pp. F1050-F1059 ◽  
Author(s):  
Mark Wareing ◽  
Carole J. Ferguson ◽  
Mathieu Delannoy ◽  
Alan G. Cox ◽  
Raymond F. T. McMahon ◽  
...  
Keyword(s):  
Excretion Rate ◽  
Iron Concentration ◽  
Dietary Iron ◽  
Iron Intake ◽  
Restricted Diet ◽  
Output Rate ◽  
Cellular Machinery ◽  
Excretion Rates ◽  
Subapical Region ◽  
Iron Excretion

Divalent metal transporter1 (DMT1; also known as DCT1 or NRAMP2) is an important component of the cellular machinery responsible for dietary iron absorption in the duodenum. DMT1 is also highly expressed in the kidney where it has been suggested to play a role in urinary iron handling. In this study, we determined the effect on renal DMT1 expression of feeding an iron-restricted diet (50 mg/kg) or an iron-enriched diet (5 g/kg) for 4 wk and measured urinary and fecal iron excretion rates. Feeding the low-iron diet caused a reduction in serum iron concentration and fecal iron output rate with an increase in renal DMT1 expression. Feeding an iron-enriched diet had the converse effect. Therefore, DMT1 expression in the kidney is sensitive to dietary iron intake, and the level of expression is inversely related to the dietary iron content. Changes in DMT1 expression occurred intracellularly in the proximal tubule and in the apical membrane and subapical region of the distal convoluted tubule. Increased DMT1 expression was accompanied by a decrease in urinary iron excretion rate and vice versa when DMT1 expression was reduced. Together, these findings suggest that modulation of renal DMT1 expression may influence renal iron excretion rate.

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