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• W2116806091 abstract "ZIP14 is a transmembrane metal ion transporter that is abundantly expressed in the liver, heart, and pancreas. Previous studies of HEK 293 cells and the hepatocyte cell lines AML12 and HepG2 established that ZIP14 mediates the uptake of non-transferrin-bound iron, a form of iron that appears in the plasma during pathologic iron overload. In this study we investigated the role of ZIP14 in the cellular assimilation of iron from transferrin, the circulating plasma protein that normally delivers iron to cells by receptor-mediated endocytosis. We also determined the subcellular localization of ZIP14 in HepG2 cells. We found that overexpression of ZIP14 in HEK 293T cells increased the assimilation of iron from transferrin without increasing levels of transferrin receptor 1 or the uptake of transferrin. To allow for highly specific and sensitive detection of endogenous ZIP14 in HepG2 cells, we used a targeted knock-in approach to generate a cell line expressing a FLAG-tagged ZIP14 allele. Confocal microscopic analysis of these cells detected ZIP14 at the plasma membrane and in endosomes containing internalized transferrin. HepG2 cells in which endogenous ZIP14 was suppressed by siRNA assimilated 50% less iron from transferrin compared with controls. The uptake of transferrin, however, was unaffected. We also found that ZIP14 can mediate the transport of iron at pH 6.5, the pH at which iron dissociates from transferrin within the endosome. These results suggest that endosomal ZIP14 participates in the cellular assimilation of iron from transferrin, thus identifying a potentially new role for ZIP14 in iron metabolism. ZIP14 is a transmembrane metal ion transporter that is abundantly expressed in the liver, heart, and pancreas. Previous studies of HEK 293 cells and the hepatocyte cell lines AML12 and HepG2 established that ZIP14 mediates the uptake of non-transferrin-bound iron, a form of iron that appears in the plasma during pathologic iron overload. In this study we investigated the role of ZIP14 in the cellular assimilation of iron from transferrin, the circulating plasma protein that normally delivers iron to cells by receptor-mediated endocytosis. We also determined the subcellular localization of ZIP14 in HepG2 cells. We found that overexpression of ZIP14 in HEK 293T cells increased the assimilation of iron from transferrin without increasing levels of transferrin receptor 1 or the uptake of transferrin. To allow for highly specific and sensitive detection of endogenous ZIP14 in HepG2 cells, we used a targeted knock-in approach to generate a cell line expressing a FLAG-tagged ZIP14 allele. Confocal microscopic analysis of these cells detected ZIP14 at the plasma membrane and in endosomes containing internalized transferrin. HepG2 cells in which endogenous ZIP14 was suppressed by siRNA assimilated 50% less iron from transferrin compared with controls. The uptake of transferrin, however, was unaffected. We also found that ZIP14 can mediate the transport of iron at pH 6.5, the pH at which iron dissociates from transferrin within the endosome. These results suggest that endosomal ZIP14 participates in the cellular assimilation of iron from transferrin, thus identifying a potentially new role for ZIP14 in iron metabolism. IntroductionMost cells acquire iron from transferrin (TF), 2The abbreviations used are: TFtransferrinAAVadeno-associated virusDMT1divalent metal transporter 1EEA1early endosome antigen 1Fe-TFiron-transferrinNTBInon-transferrin-bound ironSFMserum-free mediumTBItransferrin-bound ironTFRtransferrin receptorZIP14ZRT/IRT-like protein 14. a circulating plasma protein that can carry up to two ferric (Fe3+) iron atoms. After Fe-TF binds to cell surface TF receptor 1 (TFR1), the plasma membrane invaginates into clathrin-coated pits, which internalize the Fe-TF·TFR1 complex into endosomes. Upon endosomal acidification, Fe3+ is released and subsequently reduced to Fe2+. The liberated Fe2+ is then transported across the endosomal membrane and into the cytosol (1Graham R.M. Chua A.C. Herbison C.E. Olynyk J.K. Trinder D. World J. Gastroenterol. 2007; 13: 4725-4736Crossref PubMed Scopus (98) Google Scholar).The assimilation of iron from TF has been best characterized in developing erythroid cells, the most avid consumers of TF-bound iron (TBI). In these cells, reduction of Fe3+ is catalyzed by the oxidoreductase Steap3 (2Ohgami R.S. Campagna D.R. Greer E.L. Antiochos B. McDonald A. Chen J. Sharp J.J. Fujiwara Y. Barker J.E. Fleming M.D. Nat. Genet. 2005; 37: 1264-1269Crossref PubMed Scopus (480) Google Scholar), and iron transport out of the endosome is facilitated by the transmembrane protein divalent metal transporter 1 (DMT1) (3Fleming M.D. Romano M.A. Su M.A. Garrick L.M. Garrick M.D. Andrews N.C. Proc. Natl. Acad. Sci. U.S.A. 1998; 95: 1148-1153Crossref PubMed Scopus (801) Google Scholar, 4Su M.A. Trenor C.C. Fleming J.C. Fleming M.D. Andrews N.C. Blood. 1998; 92: 2157-2163Crossref PubMed Google Scholar). Accordingly, mice lacking either Steap3 or DMT1 cannot incorporate sufficient iron into developing erythrocytes and become anemic (2Ohgami R.S. Campagna D.R. Greer E.L. Antiochos B. McDonald A. Chen J. Sharp J.J. Fujiwara Y. Barker J.E. Fleming M.D. Nat. Genet. 2005; 37: 1264-1269Crossref PubMed Scopus (480) Google Scholar, 3Fleming M.D. Romano M.A. Su M.A. Garrick L.M. Garrick M.D. Andrews N.C. Proc. Natl. Acad. Sci. U.S.A. 1998; 95: 1148-1153Crossref PubMed Scopus (801) Google Scholar). After the erythroid marrow, the second largest consumer of TBI is the liver, accounting for 10–20% of iron exchange with the plasma (5Cheney B.A. Lothe K. Morgan E.H. Sood S.K. Finch C.A. Am. J. Physiol. 1967; 212: 376-380Crossref PubMed Scopus (21) Google Scholar). Interestingly, anemic Steap3-mutant mice or DMT1-null mice are able to take up iron into the liver (6Gunshin H. Fujiwara Y. Custodio A.O. Direnzo C. Robine S. Andrews N.C. J. Clin. Invest. 2005; 115: 1258-1266Crossref PubMed Scopus (306) Google Scholar, 7Lambe T. Simpson R.J. Dawson S. Bouriez-Jones T. Crockford T.L. Lepherd M. Latunde-Dada G.O. Robinson H. Raja K.B. Campagna D.R. Villarreal Jr., G. Ellory J.C. Goodnow C.C. Fleming M.D. McKie A.T. Cornall R.J. Blood. 2009; 113: 1805-1808Crossref PubMed Scopus (68) Google Scholar), indicating that Steap3 and DMT1 are dispensable for hepatic iron uptake.Under normal conditions, >95% of plasma iron is TBI. Studies in perfused rat liver document that the liver takes up TBI, almost exclusively into hepatocytes (8Morgan E.H. Smith G.D. Peters T.J. Biochem. J. 1986; 237: 163-173Crossref PubMed Scopus (41) Google Scholar). In iron overload conditions, such as hereditary hemochromatosis, the liver can also take up non-TF-bound iron (NTBI), a form of iron that appears in the plasma when the iron-carrying capacity of TF becomes exceeded (9Chua A.C. Olynyk J.K. Leedman P.J. Trinder D. Blood. 2004; 104: 1519-1525Crossref PubMed Scopus (70) Google Scholar). The uptake of NTBI into hepatocyte cell lines is mediated, at least in part, by the transmembrane protein ZIP14, a member of the ZIP family of metal ion transporters (10Gao J. Zhao N. Knutson M.D. Enns C.A. J. Biol. Chem. 2008; 283: 21462-21468Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 11Liuzzi J.P. Aydemir F. Nam H. Knutson M.D. Cousins R.J. Proc. Natl. Acad. Sci. U.S.A. 2006; 103: 13612-13617Crossref PubMed Scopus (401) Google Scholar). Recently, we found that expression of HFE, the hemochromatosis protein, in HepG2 cells decreased ZIP14 levels, apparently by decreasing ZIP14 stability (10Gao J. Zhao N. Knutson M.D. Enns C.A. J. Biol. Chem. 2008; 283: 21462-21468Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar). Importantly, the reduction in ZIP14 was associated with not only a diminished uptake of NTBI but also a decrease in the assimilation of iron from TF, suggesting that ZIP14 participates in both pathways of iron acquisition. In the present study, we investigated the role of ZIP14 in the cellular assimilation of iron from TF, the pH dependence of ZIP14-mediated iron uptake, and the subcellular localization of endogenous ZIP14. We found that overexpression of ZIP14 increased the assimilation of iron from TF and enhanced cellular iron uptake at pH 7.5 and 6.5. Endogenous ZIP14 in HepG2 cells localized to the plasma membrane and partially co-localized with endosomes containing internalized Fe-TF. Moreover, siRNA-mediated knockdown of endogenous ZIP14 decreased the assimilation of iron from TF without decreasing the uptake of TF or the levels of TFR1. These results suggest that ZIP14 participates in the assimilation of iron from TF in addition to playing a role in NTBI uptake.DISCUSSIONZIP14 is a transmembrane protein that belongs to the solute carrier 39 (SLC39A) family, which includes 14 known mammalian members. ZIP14 was first characterized in 2005 by Taylor et al. (17Taylor K.M. Morgan H.E. Johnson A. Nicholson R.I. FEBS Lett. 2005; 579: 427-432Crossref PubMed Scopus (123) Google Scholar), who showed that ZIP14 overexpression in Chinese hamster ovary (CHO) cells stimulated the uptake of zinc into the cytosol. In 2006, Liuzzi et al. (11Liuzzi J.P. Aydemir F. Nam H. Knutson M.D. Cousins R.J. Proc. Natl. Acad. Sci. U.S.A. 2006; 103: 13612-13617Crossref PubMed Scopus (401) Google Scholar) reported that overexpression of ZIP14 in HEK 293 cells and Sf9 insect cells enhanced not only the uptake of zinc, but also iron. The iron was presented to the cells as ferric citrate, the major form of NTBI that appears in plasma in conditions of iron overload (22Grootveld M. Bell J.D. Halliwell B. Aruoma O.I. Bomford A. Sadler P.J. J. Biol. Chem. 1989; 264: 4417-4422Abstract Full Text PDF PubMed Google Scholar). In addition, suppression of endogenous ZIP14 with siRNA in AML12 cells, a mouse hepatocyte cell line, resulted in reduced uptake of NTBI from ferric citrate. Subsequently, Gao et al. (10Gao J. Zhao N. Knutson M.D. Enns C.A. J. Biol. Chem. 2008; 283: 21462-21468Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar) showed that ZIP14 overexpression stimulated NTBI uptake in HeLa cells and that suppression of endogenous ZIP14 in the human hepatoma cell line, HepG2, decreased NTBI uptake. Together, these data provide strong support that ZIP14 mediates NTBI uptake into cells (Fig. 8). A physiologic role for ZIP14 in NTBI uptake is suggested by the observation that human ZIP14 is expressed most abundantly in liver, heart, and pancreas (17Taylor K.M. Morgan H.E. Johnson A. Nicholson R.I. FEBS Lett. 2005; 579: 427-432Crossref PubMed Scopus (123) Google Scholar), the tissues that preferentially accumulate iron in iron overload disorders such as hereditary hemochromatosis.In addition to clearing NTBI rapidly, the liver readily takes up TBI and assimilates the iron (8Morgan E.H. Smith G.D. Peters T.J. Biochem. J. 1986; 237: 163-173Crossref PubMed Scopus (41) Google Scholar). Studies in isolated primary mouse and rat hepatocytes have shown that TBI can inhibit the uptake of NTBI (and vice versa), suggesting that NTBI and TBI share a common membrane iron transporter (9Chua A.C. Olynyk J.K. Leedman P.J. Trinder D. Blood. 2004; 104: 1519-1525Crossref PubMed Scopus (70) Google Scholar, 23Graham R.M. Morgan E.H. Baker E. Eur. J. Biochem. 1998; 253: 139-145Crossref PubMed Scopus (25) Google Scholar, 24Trinder D. Morgan E. Hepatology. 1997; 26: 691-698Crossref PubMed Scopus (25) Google Scholar). Our previous study in HepG2 cells suggested that ZIP14 may represent this common transporter. Specifically, we found that HFE expression resulted in a down-regulation of ZIP14 that was associated with reduced uptake and assimilation of iron when the iron was presented to the cells as either NTBI or TBI (10Gao J. Zhao N. Knutson M.D. Enns C.A. J. Biol. Chem. 2008; 283: 21462-21468Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar).In the present study we tested the hypothesis that ZIP14 plays a role in the assimilation of iron from TF. First, we found that transfection of HEK 293T cells with ZIP14 stimulated the assimilation of iron from TF. The enhanced assimilation of iron was not associated with changes in the levels of TFR1 or DMT1, which could also affect this process. These data suggest that ZIP14, rather than TFR1 or DMT1, is limiting for iron assimilation by this pathway in HEK 293T cells. That DMT1 is not limiting is further supported by the observation that the assimilation of iron from TF was unaffected in HEK 293T cells stably transfected with DMT1 (25Wetli H.A. Buckett P.D. Wessling-Resnick M. Chem. Biol. 2006; 13: 965-972Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar). A similar lack of an effect of DMT1 transfection on the assimilation of iron from TF has also been observed in CHO cells (26Zhang A.S. Canonne-Hergaux F. Gruenheid S. Gros P. Ponka P. Exp. Hematol. 2008; 36: 1227-1235Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar) and in the human hepatoma cell line HLF (27Shindo M. Torimoto Y. Saito H. Motomura W. Ikuta K. Sato K. Fujimoto Y. Kohgo Y. Hepatol. Res. 2006; 35: 152-162PubMed Google Scholar).As in human liver, ZIP14 is abundantly expressed in HepG2 cells, a human hepatoma cell line that possesses many of the key features of hepatocytes (18Bokhari M. Carnachan R.J. Cameron N.R. Przyborski S.A. J. Anat. 2007; 211: 567-576PubMed Google Scholar). Hepatocytes and hepatoma cells are known to take up Fe-TF by several mechanisms including a high affinity, low capacity TFR1-mediated endocytic pathway and a low affinity, high capacity TFR1-independent pathway (28Morgan E.H. Baker E. Fed. Proc. 1986; 45: 2810-2816PubMed Google Scholar, 29Ikuta K. Zak O. Aisen P. Int. J. Biochem. Cell Biol. 2004; 36: 340-352Crossref PubMed Scopus (22) Google Scholar, 30Trinder D. Morgan E.H. Baker E. Biochim. Biophys. Acta. 1988; 943: 440-446Crossref PubMed Scopus (40) Google Scholar, 31Trinder D. Zak O. Aisen P. Hepatology. 1996; 23: 1512-1520Crossref PubMed Google Scholar). In primary mouse hepatocytes and HuH7 hepatoma cells, the TFR1-mediated pathway saturates at low TF concentrations between 50 and 100 nm (31Trinder D. Zak O. Aisen P. Hepatology. 1996; 23: 1512-1520Crossref PubMed Google Scholar, 32Chua A.C. Herbison C.E. Drake S.F. Graham R.M. Olynyk J.K. Trinder D. Hepatology. 2008; 47: 1737-1744Crossref PubMed Scopus (19) Google Scholar). Here, we document that in HepG2 cells incubated with 100 nm TF, knockdown of endogenous ZIP14-FLAG resulted in 45% less assimilation of iron from TF compared with controls. A similar decrement in iron assimilation from 100 nm TF was observed in wild-type HepG2 cells in which ZIP14 expression was suppressed (supplemental Fig. S1). These data provide strong support that ZIP14 plays a role in the assimilation of iron from TF, presumably through the high affinity, low capacity TFR1-mediated endocytic pathway (Fig. 8). Consistent with this possibility is the observation that endogenous ZIP14 in HepG2 cells partially co-localizes with endocytosed holo-TF, the early endosome marker EEA1, and TFR1. Moreover, ZIP14 is able to mediate the transport of iron at pH 6.5, the pH at which more than 50% of iron dissociates from TF in the endosome (33Núñez M.T. Gaete V. Watkins J.A. Glass J. J. Biol. Chem. 1990; 265: 6688-6692Abstract Full Text PDF PubMed Google Scholar).ZIP14 also partially co-localized with LAMP1, a marker for late endosomes and lysosomes, which usually have a pH of <6.0. Because ZIP14 does not appear to transport iron at pH 5.5, it seems unlikely that ZIP14 would function as an iron transporter in these more acidic organelles. A more effective transporter under lower pH conditions would be DMT1, which transports iron optimally at pH 5.5 (34Gunshin H. Mackenzie B. Berger U.V. Gunshin Y. Romero M.F. Boron W.F. Nussberger S. Gollan J.L. Hediger M.A. Nature. 1997; 388: 482-488Crossref PubMed Scopus (2632) Google Scholar) and which localizes to late endosomes and lysosomes (35Tabuchi M. Yoshimori T. Yamaguchi K. Yoshida T. Kishi F. J. Biol. Chem. 2000; 275: 22220-22228Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar).Recently, Herbison et al. (36Herbison C.E. Thorstensen K. Chua A.C. Graham R.M. Leedman P. Olynyk J.K. Trinder D. Am. J. Physiol. Cell Physiol. 2009; 297: C1567-C1575Crossref PubMed Scopus (54) Google Scholar) showed that knockdown of TFR1 in HuH7 cells resulted in 80% less assimilation of iron from 50 nm TF compared with controls. The lower iron levels were due to diminished uptake of TF because TF uptake was also 80% lower. In our study, knockdown of ZIP14 in HepG2 cells did not affect the uptake of TF, but it did reduce the assimilation of iron from TF by 50%. These data indicate that ZIP14 is required for efficient cellular assimilation of iron from internalized TF.In humans, plasma TF concentrations typically range between 25 and 50 μm. Saturation of TF with iron normally fluctuates between 20 and 55%, but can reach 100% in iron overload. At physiologic concentrations of TF, hepatocytes can take up TBI via a TFR1-independent pathway (29Ikuta K. Zak O. Aisen P. Int. J. Biochem. Cell Biol. 2004; 36: 340-352Crossref PubMed Scopus (22) Google Scholar, 31Trinder D. Zak O. Aisen P. Hepatology. 1996; 23: 1512-1520Crossref PubMed Google Scholar, 37Trinder D. Morgan E. Baker E. Hepatology. 1986; 6: 852-858Crossref PubMed Scopus (57) Google Scholar). The molecular mechanisms involved in this pathway, however, remain poorly defined.The ability of ZIP14 to enhance the assimilation of iron from TF may be relevant to the hypoferremia (and anemia) of inflammation. In response to inflammatory stimuli, such as lipopolysaccharide (LPS) or turpentine, plasma iron levels rapidly decrease and hepatic iron levels increase (38Nemeth E. Rivera S. Gabayan V. Keller C. Taudorf S. Pedersen B.K. Ganz T. J. Clin. Invest. 2004; 113: 1271-1276Crossref PubMed Scopus (1962) Google Scholar, 39Sheikh N. Dudas J. Ramadori G. Lab. Invest. 2007; 87: 713-725Crossref PubMed Scopus (74) Google Scholar). The hypoferremia results predominantly from a blockade of iron release from reticuloendothelial macrophages, the main suppliers of iron to the plasma (40Knutson M. Wessling-Resnick M. Crit. Rev. Biochem. Mol. Biol. 2003; 38: 61-88Crossref PubMed Scopus (254) Google Scholar). Because the liver houses the largest population of reticuloendothelial macrophages (i.e. Kupffer cells), hepatic iron levels increase. During inflammation, iron release is also reduced from hepatocytes, further elevating hepatic iron concentrations. Increased hepatic uptake of plasma iron, which is normally >95% TBI, may additionally contribute to the hypoferremia of inflammation. Studies in isolated rat hepatocytes have shown that LPS markedly increases the assimilation of iron from internalized TF (41Potter B.J. Blades B. McHugh T.A. Nunes R.M. Beloqui O. Slott P.A. Rand J.H. Am. J. Physiol. Gastrointest. Liver Physiol. 1989; 257: G524-G531Crossref PubMed Google Scholar). Similarly in HepG2 cells, stimulation with the inflammatory cytokine, interleukin-6 (IL-6), enhanced the assimilation of iron from TF by 48% (42Hirayama M. Kohgo Y. Kondo H. Shintani N. Fujikawa K. Sasaki K. Kato J. Niitsu Y. Hepatology. 1993; 18: 874-880Crossref PubMed Scopus (97) Google Scholar). Because LPS, turpentine, and IL-6 have all been shown to increase levels of ZIP14 potently in mouse liver and in isolated hepatocytes (19Liuzzi J.P. Lichten L.A. Rivera S. Blanchard R.K. Aydemir T.B. Knutson M.D. Ganz T. Cousins R.J. Proc. Natl. Acad. Sci. U.S.A. 2005; 102: 6843-6848Crossref PubMed Scopus (432) Google Scholar), it is possible that ZIP14 contributes to the hypoferremia of inflammation by stimulating the assimilation of iron from plasma TF.Until now, DMT1 was the only transmembrane transport protein that has been proposed to participate in hepatocyte assimilation of iron from TF (1Graham R.M. Chua A.C. Herbison C.E. Olynyk J.K. Trinder D. World J. Gastroenterol. 2007; 13: 4725-4736Crossref PubMed Scopus (98) Google Scholar). Data from the present study suggest that ZIP14, which is expressed in HepG2 cells at 10 times higher levels than DMT1, participates in the assimilation of iron from TF. Future studies in whole animals will be needed to define the in vivo role of ZIP14 in iron uptake by the liver and other tissues/cell types. Of particular interest is the placenta, which has been shown to express ZIP14 (17Taylor K.M. Morgan H.E. Johnson A. Nicholson R.I. FEBS Lett. 2005; 579: 427-432Crossref PubMed Scopus (123) Google Scholar). Placental iron transport involves endocytosis of TF from the maternal circulation and dissociation of iron from TF prior to export into the fetal circulation (43McArdle H.J. Andersen H.S. Jones H. Gambling L. J. Neuroendocrinol. 2008; 20: 427-431Crossref PubMed Scopus (79) Google Scholar). The transport of iron out of the endosome in syncytiotrophoblast cells of the placenta was thought to be mediated by DMT1 (44Georgieff M.K. Wobken J.K. Welle J. Burdo J.R. Connor J.R. Placenta. 2000; 21: 799-804Crossref PubMed Scopus (89) Google Scholar), until the generation of DMT1 knock-out mice demonstrated that it was not required (6Gunshin H. Fujiwara Y. Custodio A.O. Direnzo C. Robine S. Andrews N.C. J. Clin. Invest. 2005; 115: 1258-1266Crossref PubMed Scopus (306) Google Scholar). If ZIP14 localizes to endosomes in syncytiotrophoblast cells as it does in HepG2 cells, it seems plausible that ZIP14 plays a role in placental iron transfer. IntroductionMost cells acquire iron from transferrin (TF), 2The abbreviations used are: TFtransferrinAAVadeno-associated virusDMT1divalent metal transporter 1EEA1early endosome antigen 1Fe-TFiron-transferrinNTBInon-transferrin-bound ironSFMserum-free mediumTBItransferrin-bound ironTFRtransferrin receptorZIP14ZRT/IRT-like protein 14. a circulating plasma protein that can carry up to two ferric (Fe3+) iron atoms. After Fe-TF binds to cell surface TF receptor 1 (TFR1), the plasma membrane invaginates into clathrin-coated pits, which internalize the Fe-TF·TFR1 complex into endosomes. Upon endosomal acidification, Fe3+ is released and subsequently reduced to Fe2+. The liberated Fe2+ is then transported across the endosomal membrane and into the cytosol (1Graham R.M. Chua A.C. Herbison C.E. Olynyk J.K. Trinder D. World J. Gastroenterol. 2007; 13: 4725-4736Crossref PubMed Scopus (98) Google Scholar).The assimilation of iron from TF has been best characterized in developing erythroid cells, the most avid consumers of TF-bound iron (TBI). In these cells, reduction of Fe3+ is catalyzed by the oxidoreductase Steap3 (2Ohgami R.S. Campagna D.R. Greer E.L. Antiochos B. McDonald A. Chen J. Sharp J.J. Fujiwara Y. Barker J.E. Fleming M.D. Nat. Genet. 2005; 37: 1264-1269Crossref PubMed Scopus (480) Google Scholar), and iron transport out of the endosome is facilitated by the transmembrane protein divalent metal transporter 1 (DMT1) (3Fleming M.D. Romano M.A. Su M.A. Garrick L.M. Garrick M.D. Andrews N.C. Proc. Natl. Acad. Sci. U.S.A. 1998; 95: 1148-1153Crossref PubMed Scopus (801) Google Scholar, 4Su M.A. Trenor C.C. Fleming J.C. Fleming M.D. Andrews N.C. Blood. 1998; 92: 2157-2163Crossref PubMed Google Scholar). Accordingly, mice lacking either Steap3 or DMT1 cannot incorporate sufficient iron into developing erythrocytes and become anemic (2Ohgami R.S. Campagna D.R. Greer E.L. Antiochos B. McDonald A. Chen J. Sharp J.J. Fujiwara Y. Barker J.E. Fleming M.D. Nat. Genet. 2005; 37: 1264-1269Crossref PubMed Scopus (480) Google Scholar, 3Fleming M.D. Romano M.A. Su M.A. Garrick L.M. Garrick M.D. Andrews N.C. Proc. Natl. Acad. Sci. U.S.A. 1998; 95: 1148-1153Crossref PubMed Scopus (801) Google Scholar). After the erythroid marrow, the second largest consumer of TBI is the liver, accounting for 10–20% of iron exchange with the plasma (5Cheney B.A. Lothe K. Morgan E.H. Sood S.K. Finch C.A. Am. J. Physiol. 1967; 212: 376-380Crossref PubMed Scopus (21) Google Scholar). Interestingly, anemic Steap3-mutant mice or DMT1-null mice are able to take up iron into the liver (6Gunshin H. Fujiwara Y. Custodio A.O. Direnzo C. Robine S. Andrews N.C. J. Clin. Invest. 2005; 115: 1258-1266Crossref PubMed Scopus (306) Google Scholar, 7Lambe T. Simpson R.J. Dawson S. Bouriez-Jones T. Crockford T.L. Lepherd M. Latunde-Dada G.O. Robinson H. Raja K.B. Campagna D.R. Villarreal Jr., G. Ellory J.C. Goodnow C.C. Fleming M.D. McKie A.T. Cornall R.J. Blood. 2009; 113: 1805-1808Crossref PubMed Scopus (68) Google Scholar), indicating that Steap3 and DMT1 are dispensable for hepatic iron uptake.Under normal conditions, >95% of plasma iron is TBI. Studies in perfused rat liver document that the liver takes up TBI, almost exclusively into hepatocytes (8Morgan E.H. Smith G.D. Peters T.J. Biochem. J. 1986; 237: 163-173Crossref PubMed Scopus (41) Google Scholar). In iron overload conditions, such as hereditary hemochromatosis, the liver can also take up non-TF-bound iron (NTBI), a form of iron that appears in the plasma when the iron-carrying capacity of TF becomes exceeded (9Chua A.C. Olynyk J.K. Leedman P.J. Trinder D. Blood. 2004; 104: 1519-1525Crossref PubMed Scopus (70) Google Scholar). The uptake of NTBI into hepatocyte cell lines is mediated, at least in part, by the transmembrane protein ZIP14, a member of the ZIP family of metal ion transporters (10Gao J. Zhao N. Knutson M.D. Enns C.A. J. Biol. Chem. 2008; 283: 21462-21468Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 11Liuzzi J.P. Aydemir F. Nam H. Knutson M.D. Cousins R.J. Proc. Natl. Acad. Sci. U.S.A. 2006; 103: 13612-13617Crossref PubMed Scopus (401) Google Scholar). Recently, we found that expression of HFE, the hemochromatosis protein, in HepG2 cells decreased ZIP14 levels, apparently by decreasing ZIP14 stability (10Gao J. Zhao N. Knutson M.D. Enns C.A. J. Biol. Chem. 2008; 283: 21462-21468Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar). Importantly, the reduction in ZIP14 was associated with not only a diminished uptake of NTBI but also a decrease in the assimilation of iron from TF, suggesting that ZIP14 participates in both pathways of iron acquisition. In the present study, we investigated the role of ZIP14 in the cellular assimilation of iron from TF, the pH dependence of ZIP14-mediated iron uptake, and the subcellular localization of endogenous ZIP14. We found that overexpression of ZIP14 increased the assimilation of iron from TF and enhanced cellular iron uptake at pH 7.5 and 6.5. Endogenous ZIP14 in HepG2 cells localized to the plasma membrane and partially co-localized with endosomes containing internalized Fe-TF. Moreover, siRNA-mediated knockdown of endogenous ZIP14 decreased the assimilation of iron from TF without decreasing the uptake of TF or the levels of TFR1. These results suggest that ZIP14 participates in the assimilation of iron from TF in addition to playing a role in NTBI uptake." @default.
• W2116806091 created "2016-06-24" @default.
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• W2116806091 creator A5044002256 @default.
• W2116806091 creator A5071830954 @default.
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• W2116806091 date "2010-10-01" @default.
• W2116806091 modified "2023-10-18" @default.
• W2116806091 title "ZRT/IRT-like Protein 14 (ZIP14) Promotes the Cellular Assimilation of Iron from Transferrin" @default.
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