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.

scholarly journals Oral Administration of Ginger-Derived Lipid Nanoparticles and Dmt1 siRNA Potentiates the Effect of Dietary Iron Restriction and Mitigates Pre-Existing Iron Overload in Hamp KO Mice

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1686
Author(s):  
Xiaoyu Wang ◽  
Mingzhen Zhang ◽  
Regina R. Woloshun ◽  
Yang Yu ◽  
Jennifer K. Lee ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Absorption ◽  
Hereditary Hemochromatosis ◽  
Heme Iron ◽  
Dietary Iron ◽  
Iron Loading ◽  
Body Iron ◽  
Iron Restriction ◽  
Sirna Treatment ◽  
Non Heme Iron

Intestinal iron transport requires an iron importer (Dmt1) and an iron exporter (Fpn1). The hormone hepcidin regulates iron absorption by modulating Fpn1 protein levels on the basolateral surface of duodenal enterocytes. In the genetic, iron-loading disorder hereditary hemochromatosis (HH), hepcidin production is low and Fpn1 protein expression is elevated. High Fpn1-mediated iron export depletes intracellular iron, causing a paradoxical increase in Dmt1-mediated iron import. Increased activity of both transporters causes excessive iron absorption, thus initiating body iron loading. Logically then, silencing of intestinal Dmt1 or Fpn1 could be an effective therapeutic intervention in HH. It was previously established that Dmt1 knock down prevented iron-loading in weanling Hamp (encoding hepcidin) KO mice (modeling type 2B HH). Here, we tested the hypothesis that Dmt1 silencing combined with dietary iron restriction (which may be recommended for HH patients) will mitigate iron loading once already established. Accordingly, adult Hamp KO mice were switched to a low-iron (LFe) diet and (non-toxic) folic acid-coupled, ginger nanoparticle-derived lipid vectors (FA-GDLVs) were used to deliver negative-control (NC) or Dmt1 siRNA by oral, intragastric gavage daily for 21 days. The LFe diet reduced body iron burden, and experimental interventions potentiated iron losses. For example, Dmt1 siRNA treatment suppressed duodenal Dmt1 mRNA expression (by ~50%) and reduced serum and liver non-heme iron levels (by ~60% and >85%, respectively). Interestingly, some iron-related parameters were repressed similarly by FA-GDLVs carrying either siRNA, including 59Fe (as FeCl3) absorption (~20% lower), pancreatic non-heme iron (reduced by ~65%), and serum ferritin (decreased 40–50%). Ginger may thus contain bioactive lipids that also influence iron homeostasis. In conclusion, the combinatorial approach of FA-GDLV and Dmt1 siRNA treatment, with dietary iron restriction, mitigated pre-existing iron overload in a murine model of HH.

scholarly journals Duodenal Ferroportin Expression Is Unresponsive to Dietary Iron Excess in Nursing Piglets (FS04-01-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Peng Ji ◽  
Nicole Doan ◽  
Yining Wang ◽  
Eric Nonnecke ◽  
Bo Lonnerdal
Keyword(s):  
Birth Weight ◽  
Low Birth Weight ◽  
Protein Expression ◽  
Iron Overload ◽  
Transferrin Saturation ◽  
Pig Model ◽  
Dietary Iron ◽  
Plasma Iron ◽  
High Iron ◽  
Mrna And Protein Expression

Abstract Objectives In the US, prophylactic iron supplementation without thorough screening for iron deficiency is commonly practiced in both normal weight and low birth weight infants. In a nursing pig model, we previously found that excess dietary iron results in tissue iron overload, suggesting ineffective regulation of intestinal iron absorption. Herein, we aimed to determine if hepcidin-mediated ferroportin (FPN1) degradation is functionally immature in early life. Methods Twelve nursing piglets of normal birth weight (2.1 ± 0.4 kg, PD2) were supplemented with either low (AGAL, 1 mg/d·kg body weight) or high iron (AGAH, 15 mg/d·kg BW)) in form of ferrous sulfate solution. Eight low birth weight (1.2 ± 0.4 kg on PD2) piglets were supplemented with high iron (SGAH, 15 mg/d·kg BW) from PD2 to 21. All piglets were raised by suckling their sows. Blood samples were collected weekly for analysis of hemoglobin, hematocrit, and plasma iron. Duodenal mucosa (DM) and hepatic mRNA and protein expression of iron transporters and regulators were analyzed using RT-qPCR and Western blot. Data were analyzed using PROC MIXED of SAS with CONTRAST statement for planned comparison between AGAL and high iron groups. Results In comparison with AGAL, high iron, regardless of birth weight, significantly (P < 0.05) increased hemoglobin, transferrin saturation (74% vs. 49%), and plasma iron, and resulted in iron overload in DM and liver at PD21. Hepatic mRNA expression of HAMP and FTL in DM increased 275- and 3-fold, respectively, in response to high iron, whereas DMT1 in DM and TFRC in both liver and DM decreased by 7.4-, 3.8- and 5.3-fold, respectively. Consistently, protein expression of DMT1 in DM was lower in SGAH than that in AGAL; However, both mRNA and protein expression of FPN1 in DM and liver remained unaffected by iron provision or birth weight. Conclusions Hepcidin-induced ferroportin degradation is hypo-responsive to iron excess in a nursing pig model. Funding Sources UC Davis, NIFA.

Dietary iron loading negatively affects liver mitochondrial function

Metallomics ◽  
2017 ◽  
Vol 9 (11) ◽  
pp. 1634-1644 ◽  
Author(s):  
Chiara Volani ◽  
Carolina Doerrier ◽  
Egon Demetz ◽  
David Haschka ◽  
Giuseppe Paglia ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Iron Overload ◽  
Mitochondrial Function ◽  
Dependent Manner ◽  
Dietary Iron ◽  
Ros Production ◽  
Iron Loading ◽  
Oxygen Species ◽  
Respiratory Capacity ◽  
Strain Dependent

Dietary iron overload affects liver metabolic homeostasis, reducing mitochondrial respiratory capacity, and increasing reactive oxygen species (ROS) production, in a strain-dependent manner.

scholarly journals Iron overload in urban Africans in the 1990s

Gut ◽  
1999 ◽  
Vol 45 (2) ◽  
pp. 278-283 ◽  
Author(s):  
I T Gangaidzo ◽  
V M Moyo ◽  
T Saungweme ◽  
H Khumalo ◽  
R M Charakupa ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Iron Overload ◽  
Iron Concentration ◽  
Hepatic Iron ◽  
Moderate Increase ◽  
Dietary Iron ◽  
Iron Loading ◽  
C282y Mutation ◽  
Hereditary Haemochromatosis ◽  
Iron Concentrations

BACKGROUNDIn a previously described model, heterozygotes for an African iron loading locus develop iron overload only when dietary iron is high, but homozygotes may do so with normal dietary iron. If an iron loading gene is common, then homozygotes with iron overload will be found even in an urban population where traditional beer, the source of iron, is uncommon.AIMSTo determine whether iron overload and the C282Y mutation characteristic of hereditary haemochromatosis are readily identifiable in an urban African population.METHODSHistological assessment, hepatocellular iron grading, and dry weight non-haem iron concentration were determined in post mortem tissue from liver, spleen, heart, lungs, and skin. DNA of subjects with elevated hepatic iron indexes was analysed for the C282Y mutation. Iron concentrations in other tissues were compared.RESULTSA moderate increase (>30 μmol/g) in hepatic iron concentrations was found in 31 subjects (23%; 95% confidence interval 15.9 to 30.1%), and they were considerably elevated (>180 μmol/g) in seven subjects (5.2%; 95% confidence interval 1.5 to 8.9%). Appreciably elevated hepatic iron concentrations were associated with heavy iron deposition in both hepatocytes and macrophages, and either portal fibrosis or cirrhosis. All were negative for the C282Y mutation. Very high concentrations were uncommon in subjects dying in hospital. Concentrations of iron in spleen, heart, lung, and skin were significantly higher in subjects with elevated hepatic iron.CONCLUSIONSIron overload is readily identified among urban Africans and is associated with hepatic damage and iron loading of several tissues. The condition is unrelated to the genetic mutation found in hereditary haemochromatosis.

scholarly journals Metabolic Signature of Dietary Iron Overload in a Mouse Model

Cells ◽  
2018 ◽  
Vol 7 (12) ◽  
pp. 264 ◽  
Author(s):  
Chiara Volani ◽  
Giuseppe Paglia ◽  
Sigurdur Smarason ◽  
Peter Pramstaller ◽  
Egon Demetz ◽  
...  
Keyword(s):  
Mouse Model ◽  
Iron Overload ◽  
Peripheral Blood ◽  
Iron Supplementation ◽  
High Resolution Mass Spectrometry ◽  
Krebs Cycle ◽  
Dietary Iron ◽  
Iron Loading ◽  
Metabolic Signature ◽  
Over Time

Iron is an essential co-factor for several metabolic processes, including the Krebs cycle and mitochondrial oxidative phosphorylation. Therefore, maintaining an appropriate iron balance is essential to ensure sufficient energy production and to avoid excessive reactive oxygen species formation. Iron overload impairs mitochondrial fitness; however, little is known about the associated metabolic changes. Here we aimed to characterize the metabolic signature triggered by dietary iron overload over time in a mouse model, where mice received either a standard or a high-iron diet. Metabolic profiling was assessed in blood, plasma and liver tissue. Peripheral blood was collected by means of volumetric absorptive microsampling (VAMS). Extracted blood and tissue metabolites were analyzed by liquid chromatography combined to high resolution mass spectrometry. Upon dietary iron loading we found increased glucose, aspartic acid and 2-/3-hydroxybutyric acid levels but low lactate and malate levels in peripheral blood and plasma, pointing to a re-programming of glucose homeostasis and the Krebs cycle. Further, iron loading resulted in the stimulation of the urea cycle in the liver. In addition, oxidative stress was enhanced in circulation and coincided with increased liver glutathione and systemic cysteine synthesis. Overall, iron supplementation affected several central metabolic circuits over time. Hence, in vivo investigation of metabolic signatures represents a novel and useful tool for getting deeper insights into iron-dependent regulatory circuits and for monitoring of patients with primary and secondary iron overload, and those ones receiving iron supplementation therapy.

Limited effects of combined dietary copper deficiency/iron overload on oxidative stress parameters in rat liver and plasma

2005 ◽  
Vol 16 (12) ◽  
pp. 750-756 ◽  
Author(s):  
Kevin A. Cockell ◽  
Andrew T.L. Wotherspoon ◽  
Bartholomeus Belonje ◽  
Melissa E. Fritz ◽  
René Madère ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Iron Overload ◽  
Rat Liver ◽  
Copper Deficiency ◽  
Dietary Copper ◽  
Oxidative Stress Parameters ◽  
Stress Parameters

scholarly journals Dietary Iron Intake in Excess of Requirements Impairs Intestinal Copper Absorption in Sprague Dawley Rat Dams, Causing Copper Deficiency in Suckling Pups

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 338
Author(s):  
Jennifer K. Lee ◽  
Jung-Heun Ha ◽  
James F. Collins
Keyword(s):  
Iron Supplementation ◽  
Iron Homeostasis ◽  
Dietary Iron ◽  
Sprague Dawley ◽  
Experimental Proof ◽  
Liver Iron ◽  
Copper Absorption ◽  
Hepatic Copper ◽  
Pregnancy And Lactation ◽  
Copper Depletion

Physiologically relevant iron-copper interactions have been frequently documented. For example, excess enteral iron inhibits copper absorption in laboratory rodents and humans. Whether this also occurs during pregnancy and lactation, when iron supplementation is frequently recommended, is, however, unknown. Here, the hypothesis that high dietary iron will perturb copper homeostasis in pregnant and lactating dams and their pups was tested. We utilized a rat model of iron-deficiency/iron supplementation during pregnancy and lactation to assess this possibility. Rat dams were fed low-iron diets early in pregnancy, and then switched to one of 5 diets with normal (1×) to high iron (20×) until pups were 14 days old. Subsequently, copper and iron homeostasis, and intestinal copper absorption (by oral, intragastric gavage with 64Cu), were assessed. Copper depletion/deficiency occurred in the dams and pups as dietary iron increased, as evidenced by decrements in plasma ceruloplasmin (Cp) and superoxide dismutase 1 (SOD1) activity, depletion of hepatic copper, and liver iron loading. Intestinal copper transport and tissue 64Cu accumulation were lower in dams consuming excess iron, and tissue 64Cu was also low in suckling pups. In some cases, physiological disturbances were noted when dietary iron was only ~3-fold in excess, while for others, effects were observed when dietary iron was 10–20-fold in excess. Excess enteral iron thus antagonizes the absorption of dietary copper, causing copper depletion in dams and their suckling pups. Low milk copper is a likely explanation for copper depletion in the pups, but experimental proof of this awaits future experimentation.

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