ZIP8 Is an Iron and Zinc Transporter Whose Cell-surface Expression Is Up-regulated by Cellular Iron Loading

Wang, Chia-Yu; Jenkitkasemwong, Supak; Duarte, Stephanie; Sparkman, Brian K.; Shawki, Ali; Mackenzie, Bryan; Knutson, Mitchell D.

doi:10.1074/jbc.m112.367284

Cited by 307 publications

(321 citation statements)

References 61 publications

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“…Our data indicate that DMT1 plays no physiologically relevant role in manganese absorption; however, the possibility remains that DMT1 could contribute to manganese absorption in manganese overexposure or dietary iron deficiency. Alternative intestinal uptake systems for manganese have not been identified but candidates include ZIP14 which is strongly expressed in the intestine and exhibits manganese transport activity in vitro (48,57). Consistent with the strong preference of DMT1 for iron over any other physiological substrate tested in vitro (27), our present data support the notion that intestinal DMT1 is specific to iron absorption, at least under normal physiological conditions.…”

Section: G644 Role Of Intestinal Dmt1 In Metal Homeostasissupporting

confidence: 79%

Intestinal DMT1 is critical for iron absorption in the mouse but is not required for the absorption of copper or manganese

Shawki

Anthony

Nose

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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101

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Divalent metal-ion transporter-1 (DMT1) is a widely expressed iron-preferring membrane-transport protein that serves a critical role in erythroid iron utilization. We have investigated its role in intestinal metal absorption by studying a mouse model lacking intestinal DMT1 (i.e., DMT1 int/int ). DMT1 int/int mice exhibited a profound hypochromicmicrocytic anemia, splenomegaly, and cardiomegaly. That the anemia was due to iron deficiency was demonstrated by the following observations in DMT1 int/int mice: 1) blood iron and tissue nonheme-iron stores were depleted; 2) mRNA expression of liver hepcidin (Hamp1) was depressed; and 3) intraperitoneal iron injection corrected the anemia, and reversed the changes in blood iron, nonheme-iron stores, and hepcidin expression levels. We observed decreased total iron content in multiple tissues from DMT1 int/int mice compared with DMT1 ϩ/ϩ mice but no meaningful change in copper, manganese, or zinc. DMT1 int/int mice absorbed 64 Cu and 54 Mn from an intragastric dose to the same extent as did DMT1 ϩ/ϩ mice but the absorption of 59 Fe was virtually abolished in DMT1 int/int mice. This study reveals a critical function for DMT1 in intestinal nonheme-iron absorption for normal growth and development. Further, this work demonstrates that intestinal DMT1 is not required for the intestinal transport of copper, manganese, or zinc. copper absorption; iron deficiency; iron-deficiency anemia; iron-refractive iron-deficiency anemia; manganese absorption; SLC11A2; zinc metabolism IRON DEFICIENCY is the most prevalent micronutrient deficiency worldwide (4, 50). Its deficiency leads to irondeficiency anemia, and to neurological and developmental disorders in children (3, 4). Since there exists no regulated mechanism for the excretion of iron, regulation of the whole body iron economy is achieved by tightly controlling absorption of the metal (21). Failure to regulate iron absorption in a manner appropriate to iron status is characteristic of several hereditary iron-overload disorders and iron-refractive iron-deficiency anemia (12,19,21).Divalent metal-ion transporter-1 (DMT1; reviewed in Ref. 52) is a widely expressed mammalian proton-coupled iron transporter (23,38). Mice in which the SLC11A2 gene coding for DMT1 was globally inactivated (i.e., SLC11A2 Ϫ/Ϫ ) exhibited a severe hypochromic-microcytic anemia and did not survive more than 7 days (22). A critical role for DMT1 in erythroid iron acquisition was confirmed by the following observations: 1) transfusion of red blood cells, but not parenteral iron injections, improved survival of SLC11A2 Ϫ/Ϫ mice; and 2) lethal dose-irradiated wild-type mice into which the investigators transplanted hematopoietic stem cells from SLC11A2 Ϫ/Ϫ mice exhibited defective erythropoiesis (22). The microcytic (mk) mouse and Belgrade (b) rat models, inbred strains that harbor a Gly185¡Arg mutation in DMT1 (17, 18), also exhibited an anemia phenotype. Parenteral iron injections partially improved the condition, and tissue or vesicle preparations from the m...

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Section: G644 Role Of Intestinal Dmt1 In Metal Homeostasissupporting

confidence: 79%

Intestinal DMT1 is critical for iron absorption in the mouse but is not required for the absorption of copper or manganese

Shawki

Anthony

Nose

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

Self Cite

101

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“…Post-transcriptional regulation has been reported for a number of ZIP proteins including ZIP1, 35 38 and ZIP8. 39 Precisely how these ZIP proteins are controlled post-transcriptionally is not well understood, but may involve a variety of mechanisms including translational inhibition, translational repression by miRNA, signal-induced translational activation, and mRNA localization. 40,41 Further studies are required to delineate how iron loading increases ZIP14 protein levels without affecting mRNA abundance.…”

mentioning

confidence: 99%

“…Possibilities include L-type Ca 2+ channels, 42 T-type Ca 2+ channels, 43 or perhaps ZIP8, an iron and zinc transporter 39 that was reported to be up-regulated in heart tissue of thalassemic mice. 43 The lack of an effect of iron overload on heart ZIP14 levels might be due to heart-specific regulation or to the comparatively minor degree of iron loading in this tissue.…”

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confidence: 99%

ZIP14 and DMT1 in the liver, pancreas, and heart are differentially regulated by iron deficiency and overload: implications for tissue iron uptake in iron-related disorders

et al. 2013

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ABSTRACT© F e r r a t a S t o r t i F o u n d a t i o n . Collectively, these data suggest that ZIP14 may not only function during iron overload to take up NTBI, but also under normal or iron-deficient conditions when cells take up iron via endocytosis of transferrin. The aim of the present study was to determine how iron deficiency and overload affect the expression of ZIP14 and DMT1 in the liver, pancreas, and heart. The localization of ZIP14 in liver and pancreas was also determined. Knowledge of where ZIP14 is expressed in these organs and how ZIP14 and DMT1 are regulated in vivo by iron will help us to better assess the contribution of these transporters to tissue iron uptake. Design and Methods Animals, diets, and non-heme iron determinationRats were made iron-deficient, iron-adequate, or iron-loaded as described previously. 10 Briefly, weanling (21-day-old) male Sprague-Dawley rats were fed modified AIN-93G purified diets containing iron at 10 ppm (iron deficient, FeD), 50 ppm (iron adequate, FeA), or 18,916 ppm (iron overload, FeO) for 3 weeks. Male Zip14 (Slc39a14) knockout and wild-type control mice maintained on the 129+Ter/SvJcl x C57BL/6 background 11 were analyzed at 6 weeks of age. Male and female hypotransferrinemic (hpx) mice and wild-type controls maintained on the BALB/cJ background were analyzed at 16 weeks of age. Homozygous hpx mice were given a weekly intraperitoneal injection of human apo-transferrin (0.6-1.8 mg) (EMD Chemicals). All mice consumed a commercial rodent diet containing 240 ppm iron (Teklad 7912, Harlan Laboratories). At the end of the studies, animals were anesthetized with vaporized isoflurane and sacrificed by exsanguination via the descending aorta. Tissues were harvested, immediately frozen in liquid nitrogen, and stored at -80°C until use. Animal protocols were approved by the University of Florida Institutional Animal Care and Use Committee. Tissue non-heme iron concentrations were determined colorimetrically after acid digestion of tissues. 12 Generation of ZIP14 antibodyRabbit anti-ZIP14 antiserum was generated against peptide ENEQTEEGKPSAIEVC corresponding to amino acids 138-153 of rat ZIP14. Antibodies specific to the ZIP14 peptide immunogen were affinity purified by using a peptide-agarose column of SulfoLink coupling gel (Pierce). Sample preparation and western blot analysisThe preparation of samples and western blot analysis are described in the Online Supplementary Design and Methods. Transfection, immunoprecipitation, and enzymatic deglycosylationEffectene reagent (Qiagen) was used to transiently transfect HEK 293T cells with either empty pCMV-Sport2 (control) or pCMV-Sport6 containing rat ZIP14 cDNA. To immunoprecipitate ZIP14, anti-ZIP14 antibody (400 mg) was covalently linked to AminoLink Plus Coupling Resin (Thermo Scientific) and added to a Pierce Spin Column according to the manufacturer's protocol. Immunoprecipitations were performed using the CoImmunoprecipitation Kit (Pierce) according to the manufacturer's instructions. To assess protein glycosylati...

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“…However, some Zn transporters (e.g. Znregulated transporter/Fe-regulated transporter-like proteins 8 and 14; ZIP8 and ZIP14) have recently been found to be capable of transporting Fe into mammalian cells (74,75) . Therefore, it can be speculated that when an excessive amount of Fe is consumed together with Zn in a water solution Fe may inhibit ZIP-mediated Zn transport, resulting in decreased Zn absorption and reduced Zn concentrations.…”

Section: Discussionmentioning

confidence: 99%

Mode of oral iron administration and the amount of iron habitually consumed do not affect iron absorption, systemic iron utilisation or zinc absorption in iron-sufficient infants: a randomised trial

et al. 2016

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ZIP8 Is an Iron and Zinc Transporter Whose Cell-surface Expression Is Up-regulated by Cellular Iron Loading

Cited by 307 publications

References 61 publications

Intestinal DMT1 is critical for iron absorption in the mouse but is not required for the absorption of copper or manganese

Intestinal DMT1 is critical for iron absorption in the mouse but is not required for the absorption of copper or manganese

ZIP14 and DMT1 in the liver, pancreas, and heart are differentially regulated by iron deficiency and overload: implications for tissue iron uptake in iron-related disorders

Mode of oral iron administration and the amount of iron habitually consumed do not affect iron absorption, systemic iron utilisation or zinc absorption in iron-sufficient infants: a randomised trial

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