{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T01:37:58Z","timestamp":1792460278651,"version":"4.5.0"},"reference-count":45,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2019,2,26]],"date-time":"2019-02-26T00:00:00Z","timestamp":1551139200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31772607"],"award-info":[{"award-number":["31772607"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31472102"],"award-info":[{"award-number":["31472102"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Zhejiang Provincal Key R &amp; D Project","award":["2019C02051"],"award-info":[{"award-number":["2019C02051"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>This experiment was conducted to investigate the transport characteristics of iron from ferrous bisglycinate (Fe-Gly) in intestinal cells. The divalent metal transporter 1 (DMT1)-knockout Caco-2 cell line was developed by Crispr-Cas9, and then the cells were treated with ferrous sulfate (FeSO4) or Fe-Gly to observe the labile iron pool and determine their iron transport. The results showed that the intracellular labile iron increased significantly with Fe-Gly or FeSO4 treatment, and this phenomenon was evident over a wide range of time and iron concentrations in the wild-type cells, whereas in the knockout cells it increased only after processing with high concentrations of iron for a long time (p &lt; 0.05). DMT1-knockout suppressed the synthesis of ferritin and inhibited the response of iron regulatory protein 1 (IRP-1) and IRP-2 to these two iron sources. The expression of peptide transporter 1 (PepT1) was not altered by knockout or iron treatment. Interestingly, the expression of zinc-regulated transporter (ZRT) and iron-regulated transporter (IRT)-like protein 14 (Zip14) was elevated significantly by knockout and iron treatment in wild-type cells (p &lt; 0.05). These results indicated that iron from Fe-Gly was probably mainly transported into enterocytes via DMT1 like FeSO4; Zip14 may play a certain role in the intestinal iron transport.<\/jats:p>","DOI":"10.3390\/nu11030485","type":"journal-article","created":{"date-parts":[[2019,2,26]],"date-time":"2019-02-26T11:00:44Z","timestamp":1551178844000},"page":"485","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Iron Transport from Ferrous Bisglycinate and Ferrous Sulfate in DMT1-Knockout Human Intestinal Caco-2 Cells"],"prefix":"10.3390","volume":"11","author":[{"given":"Xiaonan","family":"Yu","sequence":"first","affiliation":[{"name":"Key Laboratory of Animal Nutrition &amp; Feed Science, Zhejiang Province, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingjun","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Nutrition &amp; Feed Science, Zhejiang Province, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoxuan","family":"Ding","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Nutrition &amp; Feed Science, Zhejiang Province, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Nutrition &amp; Feed Science, Zhejiang Province, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Feng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Nutrition &amp; Feed Science, Zhejiang Province, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,2,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.cell.2010.06.028","article-title":"Two to Tango: Regulation of Mammalian Iron Metabolism","volume":"142","author":"Matthias","year":"2010","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.cell.2016.12.034","article-title":"A Red Carpet for Iron Metabolism","volume":"168","author":"Martina","year":"2017","journal-title":"Cell"},{"key":"ref_3","first-page":"485","article-title":"Iron-deficiency anemia","volume":"373","author":"Camaschella","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.aninu.2018.01.002","article-title":"Effect of different sources and levels of iron in the diet of sows on iron status in neonatal pigs","volume":"4","author":"Li","year":"2018","journal-title":"Anim. Nutr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2140","DOI":"10.2527\/2004.8272140x","article-title":"Effect of dietary trace mineral concentration and source (inorganic vs. chelated) on performance, mineral status, and fecal mineral excretion in pigs from weaning through finishing","volume":"82","author":"Creech","year":"2004","journal-title":"J. Anim. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"359","DOI":"10.3390\/nu9040359","article-title":"Mechanisms of iron uptake from ferric phosphate nanoparticles in human intestinal Caco-2 cells","volume":"9","author":"Antonio","year":"2017","journal-title":"Nutrients"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.anifeedsci.2008.07.004","article-title":"The effect of iron glycine chelate on tissue mineral levels, fecal mineral concentration, and liver antioxidant enzyme activity in weanling pigs","volume":"150","author":"Feng","year":"2009","journal-title":"Anim. Feed Sci. Technol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.1111\/jpn.12322","article-title":"Effects of iron\u2013glycine chelate on growth, carcass characteristic, liver mineral concentrations and haematological and biochemical blood parameters in broilers","volume":"99","author":"Kwiecien","year":"2015","journal-title":"J. Anim. Physiol. Anim. Nutr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/j.ecoenv.2007.04.013","article-title":"Assessing risk of heavy metals fromconsuming food grown on sewage irrigated soils and food chain transfer","volume":"69","author":"Chary","year":"2008","journal-title":"Ecotox. Environ. Saf."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.anifeedsci.2007.02.005","article-title":"Effects of iron glycine chelate on growth, haematological and immunological characteristics in weaning pigs","volume":"134","author":"Feng","year":"2007","journal-title":"Anim. Feed Sci. Technol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1007\/s12011-012-9418-5","article-title":"Effects of iron glycine chelate on growth, tissue mineral concentrations, fecal mineral excretion, and liver antioxidant enzyme activities in broilers","volume":"149","author":"Ma","year":"2012","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Zhuo, Z., Yu, X., Li, S., Fang, S., and Feng, J. (2018). Heme and non-heme iron on growth performances, blood parameters, tissue mineral concentration, and intestinal morphology of weanling pigs. Biol. Trace Elem. Res.","DOI":"10.1007\/s12011-018-1385-z"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/S0377-8401(00)00154-1","article-title":"Bioavailability of iron from amino acid complex in weanling pigs","volume":"86","author":"Yu","year":"2000","journal-title":"Anim. Feed Sci. Technol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1021\/bk-1991-0445.ch024","article-title":"Comparative Intestinal Absorption and subsequent metabolism of metal amino acid chelates and inorganic metal salts","volume":"445","author":"Ashmead","year":"1993","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"153","DOI":"10.22358\/jafs\/65704\/2014","article-title":"Ferrous bisglycinate increased iron transportation through DMT1 and PepT1 in pig intestinal epithelial cells compared with ferrous sulphate","volume":"23","author":"Liao","year":"2014","journal-title":"J. Anim. Feed Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1093\/ajcn\/76.3.577","article-title":"Iron bis-glycine chelate competes for the nonheme-iron absorption pathway","volume":"76","author":"Fernando","year":"2002","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1021\/jf049255c","article-title":"Inhibition of Iron Uptake from Iron Salts and Chelates by Divalent Metal Cations in Intestinal Epithelial Cells","volume":"53","author":"Yeung","year":"2005","journal-title":"J. Agric. Food Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1007\/s12011-014-9906-x","article-title":"Kinetics absorption characteristics of ferrous glycinate in SD rats and its impact on the relevant transport protein","volume":"158","author":"Zhuo","year":"2014","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"37923","DOI":"10.1038\/srep37923","article-title":"Digital gene expression profiling analysis of duodenum transcriptomes in SD rats administered ferrous sulfate or ferrous glycine chelate by gavage","volume":"6","author":"Zhuo","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1038\/ng0897-383","article-title":"Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene","volume":"16","author":"Fleming","year":"1997","journal-title":"Nat. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1152\/ajpgi.00160.2015","article-title":"Intestinal DMT1 is critical for iron absorption in the mouse but is not required for the absorption of copper or manganese","volume":"309","author":"Shawki","year":"2015","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1038\/41343","article-title":"Cloning and characterization of a mammalian proton-coupled metal-ion transporter","volume":"388","author":"Gunshin","year":"1997","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1136\/gut.2010.214312","article-title":"Iron sensing and signalling","volume":"61","author":"Evstatiev","year":"2012","journal-title":"Gut"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1038\/nrd.2016.248","article-title":"Targeting iron metabolism in drug discovery and delivery","volume":"16","author":"Bart","year":"2017","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1126\/science.1176326","article-title":"An E3 ligase possessing an iron- responsive hemerythrin domain is a regulator of iron homeostasis","volume":"326","author":"Salahudeen","year":"2009","journal-title":"Science"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1126\/science.1176333","article-title":"Control of iron homeostasis by an iron-regulated ubiquitin ligase","volume":"326","author":"Vashisht","year":"2009","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1146\/annurev.nutr.28.061807.155521","article-title":"Systemic iron homeostasis and the iron-responsive element\/iron-regulatory protein (IRE\/IRP) regulatory network","volume":"28","author":"Muckenthaler","year":"2008","journal-title":"Annu. Rev. Nutr."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.cmet.2007.10.006","article-title":"Iron regulatory proteins are essential for intestinal function and control key iron absorption molecules in the duodenum","volume":"7","author":"Galy","year":"2008","journal-title":"Cell Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1182\/blood-2011-04-343541","article-title":"Iron regulatory protein-1 and -2: Transcriptome-wide definition of binding mRNAs and shaping of the cellular proteome by iron regulatory proteins","volume":"118","author":"Sanchez","year":"2011","journal-title":"Blood"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"176","DOI":"10.3389\/fphar.2014.00176","article-title":"The IRP\/IRE system in vivo: Insights from mouse models","volume":"5","author":"Wilkinson","year":"2014","journal-title":"Front. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.cmet.2013.01.007","article-title":"The IRP1-HIF-2\u03b1 axis coordinates iron and oxygen sensing with erythropoiesis and iron absorption","volume":"17","author":"Anderson","year":"2013","journal-title":"Cell Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4922","DOI":"10.1073\/pnas.1314197110","article-title":"Intestinal HIF2\u03b1 promotes tissue-iron accumulation in disorders of iron overload with anemia","volume":"110","author":"Anderson","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/j.cmet.2011.08.015","article-title":"Activation of the HIF prolyl hydroxylase by the iron chaperones PCBP1 and PCBP2","volume":"14","author":"Anjali","year":"2011","journal-title":"Cell Metab."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.cmet.2008.12.012","article-title":"Intestinal hypoxia-inducible transcription factors are essential for iron absorption following iron deficiency","volume":"9","author":"Shah","year":"2009","journal-title":"Cell Metab."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.febslet.2004.12.006","article-title":"Structure-function analysis of a novel member of the LIV-1 subfamily of zinc transporters, ZIP14","volume":"579","author":"Taylor","year":"2005","journal-title":"FEBS Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"32141","DOI":"10.1074\/jbc.M110.143248","article-title":"ZRT\/IRT-like protein 14 (ZIP14) promotes the cellular assimilation of iron from transferrin","volume":"285","author":"Zhao","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"21462","DOI":"10.1074\/jbc.M803150200","article-title":"The hereditary hemo-chromatosis protein, HFE, inhibits iron uptake via down-regulation of Zip14 in HepG2 cells","volume":"283","author":"Gao","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"13612","DOI":"10.1073\/pnas.0606424103","article-title":"Zip14 (Slc39a14) mediates non-transferrin-bound iron uptake into cells","volume":"103","author":"Liuzzi","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1152\/ajpcell.00479.2010","article-title":"Zip14 is a complex broad-scope metal-ion transporter whose functional properties support roles in the cellular uptake of zinc and nontransferrin-bound iron","volume":"301","author":"Sparkman","year":"2011","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.cmet.2015.05.002","article-title":"SLC39A14 is required for the development of hepatocellular iron overload in murine models of hereditary hemochromatosis","volume":"22","author":"Supak","year":"2015","journal-title":"Cell Metab."},{"key":"ref_41","first-page":"1769","article-title":"SLC39A14 deficiency alters manganese homeostasis and excretion resulting in brain manganese accumulation and motor deficits in mice","volume":"115","author":"Supak","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5996","DOI":"10.1523\/JNEUROSCI.0285-17.2017","article-title":"Metal transporter Zip14 (Slc39a14) deletion in mice increases manganese deposition and produces neurotoxic signatures and diminished motor activity","volume":"37","author":"Aydemir","year":"2017","journal-title":"J. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"17025","DOI":"10.1038\/celldisc.2017.25","article-title":"Manganese transporter Slc39a14 deficiency revealed its key role in maintaining manganese homeostasis in mice","volume":"3","author":"Xin","year":"2017","journal-title":"Cell Discov."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"30485","DOI":"10.1074\/jbc.M112.364208","article-title":"Substrate profile and metal-ion selectivity of human divalent metal-ion transporter-1","volume":"287","author":"Illing","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"34032","DOI":"10.1074\/jbc.M112.367284","article-title":"ZIP8 is an iron and zinc transporter whose cell- surface expression is up-regulated by cellular iron loading","volume":"287","author":"Wang","year":"2012","journal-title":"J. Biol. Chem."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/11\/3\/485\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:34:44Z","timestamp":1760186084000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/11\/3\/485"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,2,26]]},"references-count":45,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2019,3]]}},"alternative-id":["nu11030485"],"URL":"https:\/\/doi.org\/10.3390\/nu11030485","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,2,26]]}}}