scholarly journals Exploration of the copper-related compensatory response in the Belgrade rat model of genetic iron deficiency

2011 ◽  
Vol 301 (5) ◽  
pp. G877-G886 ◽  
Author(s):  
Lingli Jiang ◽  
Perungavur Ranganathan ◽  
Yan Lu ◽  
Changae Kim ◽  
James F. Collins
Keyword(s):  
Iron Deficiency ◽  
Rat Model ◽  
Serum Copper ◽  
Compensatory Response ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Hepatic Copper ◽  
Metal Transporter ◽  
Liver Copper ◽  
Iron Deficient

The Menkes copper ATPase (Atp7a) and metallothionein (Mt1a) are induced in the duodenum of iron-deficient rats, and serum and hepatic copper levels increase. Induction of a multi-copper ferroxidase (ceruloplasmin; Cp) has also been documented. These findings hint at an important role for Cu during iron deficiency. The intestinal divalent metal transporter 1 (Dmt1) is also induced during iron deficiency. The hypothesis that Dmt1 is involved in the copper-related compensatory response during iron deficiency was tested, utilizing a mutant Dmt1 rat model, namely the Belgrade ( b/ b) rat. Data from b/ b rats were compared with phenotypically normal, heterozygous +/ b rats. Intestinal Atp7a and Dmt1 expression was increased in b/ b rats, whereas Mt1a expression was unchanged. Serum and liver copper levels did not increase in the Belgrades nor did Cp protein or activity. The lack of fully functional Dmt1 may thus partially blunt the compensatory response to iron deficiency by 1) decreasing copper levels in enterocytes, as exemplified by a lack of Mt1a induction and a lesser induction of Atp7a, 2) abolishing the frequently described increase in liver and serum copper, and 3) attenuating the documented increase in Cp expression and activity.

Expression of the duodenal iron transporters divalent-metal transporter 1 and ferroportin 1 in iron deficiency and iron overload

2001 ◽  
Vol 120 (6) ◽  
pp. 1412-1419 ◽  
Author(s):  
Heinz Zoller ◽  
Günter Weiss ◽  
Igor Theurl ◽  
Robert O. Koch ◽  
Wolfgang Vogel ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Iron Overload ◽  
Divalent Metal ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Ferroportin 1

Pharmacokinetics of pulmonary manganese absorption: evidence for increased susceptibility to manganese loading in iron-deficient rats

2005 ◽  
Vol 288 (5) ◽  
pp. L887-L893 ◽  
Author(s):  
Elizabeth Heilig ◽  
Ramon Molina ◽  
Thomas Donaghey ◽  
Joseph D. Brain ◽  
Marianne Wessling-Resnick
Keyword(s):  
Iron Deficiency ◽  
Iron Absorption ◽  
Iron Status ◽  
Mrna Levels ◽  
Blood Clearance ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Pulmonary Uptake ◽  
Iron Deficient ◽  
Metal Absorption

High levels of airborne manganese can be neurotoxic, yet little is known about absorption of this metal via the lungs. Intestinal manganese uptake is upregulated by iron deficiency and is thought to be mediated by divalent metal transporter 1 (DMT1), an iron-regulated factor known to play a role in dietary iron absorption. To better characterize metal absorption from the lungs to the blood and test whether iron deficiency may modify this process, the pharmacokinetics of pulmonary manganese and iron absorption by control and iron-deficient rats were compared. Levels of DMT1 expression in the lungs were determined to explore potential changes induced by iron deficiency that might alter metal absorption. The pharmacokinetic curves for intratracheally instilled54Mn and59Fe were significantly different, suggesting that pulmonary uptake of the two metals involves different mechanisms. Intratracheally instilled iron-deficient rats had significantly higher blood54Mn levels, whereas blood59Fe levels were significantly reduced compared with controls. The same trend was observed when radioisotopes were delivered by intravenous injection, indicating that iron-deficient rats have altered blood clearance of manganese. In situ analysis revealed the presence of DMT1 transcripts in airway epithelium; however, mRNA levels did not change in iron deficiency. Although lung DMT1 levels and metal absorption did not appear to be influenced by iron deficiency, the differences in blood clearance of instilled manganese identified by this study support the idea that iron status can influence the potential toxicity of this metal.

scholarly journals Serum ceruloplasmin protein expression and activity increases in iron-deficient rats and is further enhanced by higher dietary copper intake

Blood ◽  
2011 ◽  
Vol 118 (11) ◽  
pp. 3146-3153 ◽  
Author(s):  
Perungavur N. Ranganathan ◽  
Yan Lu ◽  
Lingli Jiang ◽  
Changae Kim ◽  
James F. Collins
Keyword(s):  
Iron Deficiency ◽  
Protein Expression ◽  
Iron Homeostasis ◽  
Amine Oxidase ◽  
Mrna Levels ◽  
Hepatic Copper ◽  
Liver Copper ◽  
Iron Deprivation ◽  
Iron Deficient ◽  
Expression And Activity

AbstractIncreases in serum and liver copper content are noted during iron deficiency in mammals, suggesting that copper-dependent processes participate during iron deprivation. One point of intersection between the 2 metals is the liver-derived, multicopper ferroxidase ceruloplasmin (Cp) that is important for iron release from certain tissues. The current study sought to explore Cp expression and activity during physiologic states in which hepatic copper loading occurs (eg, iron deficiency). Weanling rats were fed control or low iron diets containing low, normal, or high copper for ∼ 5 weeks, and parameters of iron homeostasis were measured. Liver copper increased in control and iron-deficient rats fed extra copper. Hepatic Cp mRNA levels did not change; however, serum Cp protein was higher during iron deprivation and with higher copper consumption. In-gel and spectrophotometric ferroxidase and amine oxidase assays demonstrated that Cp activity was enhanced when hepatic copper loading occurred. Interestingly, liver copper levels strongly correlated with Cp protein expression and activity. These observations support the possibility that liver copper loading increases metallation of the Cp protein, leading to increased production of the holo enzyme. Moreover, this phenomenon may play an important role in the compensatory response to maintain iron homeostasis during iron deficiency.

Induction of arachidonate 12-lipoxygenase (Alox15) in intestine of iron-deficient rats correlates with the production of biologically active lipid mediators

2008 ◽  
Vol 294 (4) ◽  
pp. G948-G962 ◽  
Author(s):  
James F. Collins ◽  
Zihua Hu ◽  
P. N. Ranganathan ◽  
Dian Feng ◽  
Laura M. Garrick ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Iron Deficiency ◽  
Membrane Lipid ◽  
Lipid Mediators ◽  
Biologically Active ◽  
Lipid Homeostasis ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Iron Deficient ◽  
12 Lipoxygenase

To identify novel genes associated with iron metabolism, we performed gene chip studies in two models of iron deficiency: iron-deprived rats and rats deficient in the principal intestinal iron transporter, divalent metal transporter 1 (i.e., Belgrade rats). Affymetrix rat genome gene chips were utilized (RAE230) with cRNA samples derived from duodenum and jejunum of experimental and control animals. Computational analysis and statistical data reduction identified 29 candidate genes, which were induced in both models of iron deficiency. Gene ontology analysis showed enrichment for genes related to lipid homeostasis, and one gene related to this physiological process, a leukocyte type, arachidonate 12-lipoxygenase ( Alox15), was selected for further examination. TaqMan real-time PCR studies demonstrated strong induction of Alox15 throughout the small and large intestine, and in the liver of iron-deficient rats. Polyclonal antibodies were developed and utilized to demonstrate that proteins levels are significantly increased in the intestinal epithelium of iron-deprived rats. HPLC analysis revealed altered intestinal lipid metabolism indicative of Alox15 activity, which resulted in the production of biologically active lipid molecules (12-HETE, 13-HODE, and 13-HOTE). The overall effect is a perturbation of intestinal lipid homeostasis, which results in the production of lipids essentially absent in the intestine of control rats. We have thus provided mechanistic insight into the alteration in lipid metabolism that occurs during iron deficiency, in that induction of Alox15 mRNA expression may be the primary event. The resulting lipid mediators may be related to documented alterations in villus structure and cell proliferation rates in iron deficiency, or to structural alterations in membrane lipid composition.

scholarly journals Iron deficiency during pregnancy: the consequences for placental function and fetal outcome

2013 ◽  
Vol 73 (1) ◽  
pp. 9-15 ◽  
Author(s):  
Harry J. McArdle ◽  
Lorraine Gambling ◽  
Christine Kennedy
Keyword(s):  
Iron Deficiency ◽  
Basolateral Membrane ◽  
Fetal Outcome ◽  
Divalent Metal Transporter 1 ◽  
Altered Expression ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Expression Of Genes ◽  
Fetal Physiology ◽  
Short And Long Term

This review examines the importance of the placenta in iron metabolism during development and the effect of iron deficiency on maternal and fetal physiology. Iron is an essential micronutrient, required for a wide variety of biological processes. During pregnancy, the mother has to deplete her iron stores in order to provide the baby with adequate amounts. Trans-placental iron transfer involves binding transferrin (Tf)-bound iron to the Tf receptor, uptake into an endosome, acidification, release of iron through divalent metal transporter 1, efflux across the basolateral membrane through ferroportin and oxidation of Fe(II) by zyklopen. An additional haem transport system has been hypothesised, which may explain why certain gene knockouts are not lethal for the developing fetus. Iron deficiency is a common phenomenon during pregnancy, and the placenta adapts by up-regulating its transfer systems, maintaining iron at the expense of the mother. Despite these adaptations, deficiency cannot be completely prevented, and the offspring suffers both short- and long-term consequences. Some of these, at least, may arise from decreased expression of genes involved in the cell cycle and altered expression of transcription factors, such as c-myc, which in turn can produce, for example, kidneys with reduced numbers of nephrons. The mechanism whereby these changes are induced is not certain, but may simply be as a result of the reduced availability of iron resulting in decreased enzyme activity. Since these changes are so significant, and because some of the changes are irreversible, we believe that iron prophylaxis should be considered in all pregnancies.

scholarly journals Intestinal ferritinophagy is regulated by HIF-2α and is essential for systemic iron homeostasis

2020 ◽  
Author(s):  
Nupur K Das ◽  
Amanda Sankar ◽  
Andrew J Schwartz ◽  
Sumeet Solanki ◽  
Xiaoya Ma ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Iron Homeostasis ◽  
Iron Absorption ◽  
Whole Body ◽  
Null Mouse ◽  
Divalent Metal Transporter 1 ◽  
Intestinal Iron Absorption ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Iron Sequestration

AbstractIron is critical for many processes including oxygen transport and erythropoiesis. Transcriptomic analysis demonstrates that HIF-2α regulates over 90% of all transcripts induced following iron deficiency in the intestine. However, beyond divalent metal transporter 1 (DMT1), ferroportin 1 (Fpn1) and duodenal cytochrome b (Dcytb), no other genes/pathways have been critically assessed with respects to their importance in intestinal iron absorption. Ferritinophagy is associated with cargo specific autophagic breakdown of ferritin and subsequent release of iron. We show here that nuclear receptor co-activator 4 (NCOA4)-mediated intestinal ferritinophagy is integrated to systemic iron demand via HIF-2α. Duodenal NCOA4 expression is regulated by HIF-2α during high systemic iron demands. Moreover, overexpression of intestinal HIF-2α is sufficient to activate NCOA4 and promote lysosomal degradation of ferritin. Promoter analysis revealed NCOA4 as a direct HIF-2α target. To demonstrate the importance of intestinal HIF-2α/ferritinophagy axis in systemic iron homeostasis, whole body and intestine-specific NCOA4-null mouse lines were assessed. These analyses demonstrate an iron sequestration in the enterocytes, and significantly high tissue ferritin levels in the dietary iron deficiency and acute hemolytic anemia models. Together, our data suggests efficient ferritinophagy is critical for intestinal iron absorption and systemic iron homeostasis.

scholarly journals Divalent Metal Transporter 1 Knock-Down Modulates IL-1β Mediated Pancreatic Beta-Cell Pro-Apoptotic Signaling Pathways through the Autophagic Machinery

2021 ◽  
Vol 22 (15) ◽  
pp. 8013
Author(s):  
Taewook Kang ◽  
Honggang Huang ◽  
Thomas Mandrup-Poulsen ◽  
Martin R. Larsen
Keyword(s):  
Cell Death ◽  
Divalent Metal ◽  
Β Cells ◽  
Β Cell ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Knock Down ◽  
Metal Transporter ◽  
Cell Functions ◽  
Protective Proteins

Pro-inflammatory cytokines promote cellular iron-import through enhanced divalent metal transporter-1 (DMT1) expression in pancreatic β-cells, consequently cell death. Inhibition of β-cell iron-import by DMT1 silencing protects against apoptosis in animal models of diabetes. However, how alterations of signaling networks contribute to the protective action of DMT1 knock-down is unknown. Here, we performed phosphoproteomics using our sequential enrichment strategy of mRNA, protein, and phosphopeptides, which enabled us to explore the concurrent molecular events in the same set of wildtype and DMT1-silenced β-cells during IL-1β exposure. Our findings reveal new phosphosites in the IL-1β-induced proteins that are clearly reverted by DMT1 silencing towards their steady-state levels. We validated the levels of five novel phosphosites of the potential protective proteins using parallel reaction monitoring. We also confirmed the inactivation of autophagic flux that may be relevant for cell survival induced by DMT1 silencing during IL-1β exposure. Additionally, the potential protective proteins induced by DMT1 silencing were related to insulin secretion that may lead to improving β-cell functions upon exposure to IL-1β. This global profiling has shed light on the signal transduction pathways driving the protection against inflammation-induced cell death in β-cells after DMT1 silencing.

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