Molecular Mediators Governing Iron-Copper Interactions

Güleç, Şükrü; Collins, James F.

doi:10.1146/annurev-nutr-071812-161215

Cited by 96 publications

(77 citation statements)

References 122 publications

(165 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Given these facts, it was logical to postulate that copper influences intestinal iron transport. This would, in fact, not be surprising, given the well-established iron-copper interactions in mammals that have been noted previously 12–14 . Exactly how, and if, dietary copper affects intestinal iron absorption has, however, not been definitively established.…”

Section: Introductionmentioning

confidence: 66%

Knockdown of copper-transporting ATPase 1 (Atp7a) impairs iron flux in fully-differentiated rat (IEC-6) and human (Caco-2) intestinal epithelial cells

Doguer

Collins

2016

Metallomics

Self Cite

View full text Add to dashboard Cite

Intestinal iron absorption is highly regulated since no mechanism for iron excretion exists. We previously demonstrated that expression of an intestinal copper transporter (Atp7a) increases in parallel with genes encoding iron transporters in the rat duodenal epithelium during iron deprivation (Am J Physiol GI/Liv Physiol. 288:G964-71, 2005). This led us to postulate that Atp7a may influence intestinal iron flux. Therefore, to test the hypothesis that Atp7a is required for optimal iron transport, we silenced Atp7a in rat IEC-6 and human Caco-2 cells. Iron transport was subsequently quantified in fully-differentiated cells plated on collagen-coated, trans-well inserts. Interestingly, 59Fe uptake and efflux were impaired in both cell lines by Atp7a silencing. Concurrent changes in the expression of key iron transport-related genes were also noted in IEC-6 cells. Expression of Dmt1 (the iron importer), Dcytb (an apical membrane ferrireductase) and Fpn1 (the iron exporter) was decreased in Atp7a knockdown (KD) cells. Paradoxically, cell-surface ferrireductase activity increased (>5-fold) in Atp7a KD cells despite decreased Dcytb mRNA expression. Moreover, increased expression (>10-fold) of hephaestin (an iron oxidase involved in iron efflux) was associated with increased ferroxidase activity in KD cells. Increases in ferrireductase and ferroxidase activity may be compensatory responses to increase iron flux. In summary, in these reductionist models of the mammalian intestinal epithelium, Atp7a KD altered expression of iron transporters and impaired iron flux. Since Atp7a is a copper transporter, it is a logical supposition that perturbations in intracellular copper homeostasis underlie the noted biologic changes in these cell lines.

show abstract

Section: Introductionmentioning

confidence: 66%

Knockdown of copper-transporting ATPase 1 (Atp7a) impairs iron flux in fully-differentiated rat (IEC-6) and human (Caco-2) intestinal epithelial cells

Doguer

Collins

2016

Metallomics

Self Cite

View full text Add to dashboard Cite

show abstract

“…Micronutrient profiling revealed a robust decrease in iron content of breast milk in mice with an intestinal disruption of HIF-2α. Although iron levels have been shown to be important in regulation of other micronutrients, no significant change was observed in any other metals assessed (45). DMT-1, FPN, and TFR-1 are expressed in the mammary gland and transport iron to milk.…”

Section: Discussionmentioning

confidence: 83%

Maternal intestinal HIF-2α is necessary for sensing iron demands of lactation in mice

Ramakrishnan

Anderson

Martin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The mechanisms that are essential for the maintenance of nutrient status in breast milk are unclear. Our data demonstrate that the intestine via hypoxia-inducible factor (HIF)-2α is an essential regulatory mechanism for maintaining the quality of breast milk. During lactation, intestinal HIF-2α is highly increased, leading to an adaptive induction of apical and basolateral iron transport genes. Disruption of intestinal HIF-2α (but not HIF-1α) or the downstream target gene divalent metal transporter (DMT)-1 in lactating mothers did not alter systemic iron homeostasis in the mothers, but led to anemia, decreased growth, and truncal alopecia in pups which was restored following weaning. Moreover, pups born from mothers with a disruption of intestinal HIF-2α led to long-term cognitive defects. Cross-fostering experiments and micronutrient profiling of breast milk demonstrated that the defects observed were due to decreased maternal iron delivery via milk. Increasing intestinal iron absorption by activation of HIF-2α or parenteral administration of iron-dextran in HIF-2α knockout mothers ameliorated anemia and restored neonatal development and adult cognitive functions. The present work details the importance of breast milk iron in neonatal development and uncovers an unexpected molecular mechanism for the regulation of nutritional status of breast milk through intestinal HIF-2α.iron homeostasis | anemia | HIF-2α | pregnancy | lactation I ron is the most abundant trace element involved in numerous biological processes such as oxygen delivery, mitochondrial respiration, and metabolism. Under normal circumstances, dietary iron provides 1-3% of the systemic iron requirement, due to an efficient recycling of iron from senesced red blood cells (1). During conditions of high iron demand, iron homeostasis relies on intestinal iron absorption (2, 3). A major systemic regulator of intestinal iron absorption is the liver-derived peptide hormone hepcidin. Hepcidin expression is regulated by systemic iron levels and in turn can regulate the only known iron exporter ferroportin (FPN) (4). This adaptive mechanism is essential for systemic iron homeostasis as evidenced in patients with iron-related disorders exhibiting decreased hepcidin expression or function (5). Moreover, mouse models with disruption of hepcidin expression, intestine specific disruption of FPN, or mice with a specific mutation of FPN with decreased hepcidin binding results in robust iron-related disorders, detailing the importance of the hepcidin-FPN axis in iron homeostasis (6-8).During pregnancy, the systemic iron requirement increase by 10-fold to support placental and fetal growth (9). Fetal and neonatal iron deficiency results in decreased growth, immunological dysfunction, anemia, and irreversible cognitive defects (10). Iron supplementation is highly recommended to prevent iron deficiency anemia during pregnancy (11). The increase in iron demand during pregnancy is met by an adaptive decrease in maternal hepcidin levels leading to enhanced iron absorption...

show abstract

“…Most hepatic copper is incorporated into the CP protein, which is subsequently secreted from hepatocytes into the blood [20]. One study compared different acute phase proteins and showed that CP is significantly increased compared to other proteins in exudative pleural effusion [21].…”

Section: Discussionmentioning

confidence: 99%

Proteomic pilot study of tuberculosis pleural effusion

Zhang

Fang

Liu

et al. 2015

BME

View full text Add to dashboard Cite

Abstract.To discuss the differences in protein expression among tuberculosis pleural effusion (TBPE), malignant pleural effusion (MPE) and transudative pleural effusion (TSPE). We recruited 50 patients with pleural effusion, including 20 TBPEs, 17 MPEs and 13 TSPEs. Using the two-dimensional electrophoresis (2-DE) and matrix-assisted laser desorption ionization-time of flight-mass spectrometry (MALDI-TOF-MS), we acquired the peptide mass finger printings (PMFs) of featured proteins. Then, we identified characteristic proteins by searching in the protein databank of the National Center of Biotechnology Information (NCBI) and assessed their diagnostic significance. We found five characteristic proteins: C1-inhibitor (C1-INH), transthyretin (TTR), human complement fragment 3b (C3b), human ceruloplasmin (CP), and Z34c protein fragment Fc (Z34c-Fc). C1-INH shows a high expression in TBPE and a low expression in MPE while TTR and C3 show low expression in TBPE and high expressions in MPE. Z34c-Fc and CP have a higher expression in TBPE than in TSPE. No common characteristic protein was found between MPE and TSPE. Statistic analysis consisted of paired t-tests and the difference between them is significance (P 0.05). C1-inhibitor (C1-INH), transthyretin (TTR), human Complement fragment 3b (C3b), human Ceruloplasmin (CP) and Z34c protein fragment Fc (Z34c-Fc) may provide an additional perspective in the differential diagnosis of PE.

show abstract

Molecular Mediators Governing Iron-Copper Interactions

Cited by 96 publications

References 122 publications

Knockdown of copper-transporting ATPase 1 (Atp7a) impairs iron flux in fully-differentiated rat (IEC-6) and human (Caco-2) intestinal epithelial cells

Knockdown of copper-transporting ATPase 1 (Atp7a) impairs iron flux in fully-differentiated rat (IEC-6) and human (Caco-2) intestinal epithelial cells

Maternal intestinal HIF-2α is necessary for sensing iron demands of lactation in mice

Proteomic pilot study of tuberculosis pleural effusion

Contact Info

Product

Resources

About