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dc.contributor.authorScheiber, Ivo Florin
dc.contributor.authorWu, Yuze
dc.contributor.authorMorgan, Shannon Elizabeth
dc.contributor.authorZhao, Ningning
dc.date.accessioned2019-07-24T18:44:27Z
dc.date.available2019-07-24T18:44:27Z
dc.date.issued2019-06-07
dc.identifier.citationScheiber, I. F., Wu, Y., Morgan, S. E., & Zhao, N. (2019). The intestinal metal transporter ZIP14 maintains systemic manganese homeostasis. Journal of Biological Chemistry, 294(23), 9147-9160.en_US
dc.identifier.issn0021-9258
dc.identifier.pmid31028174
dc.identifier.doi10.1074/jbc.RA119.008762
dc.identifier.urihttp://hdl.handle.net/10150/633493
dc.description.abstractZIP14 (encoded by the solute carrier 39 family member 14 (SLC39A14) gene) is a manganese transporter that is abundantly expressed in the liver and small intestine. Loss-of-function mutations in SLC39A14 cause severe hypermanganesemia. Because the liver is regarded as the main regulatory organ involved in manganese homeostasis, impaired hepatic manganese uptake for subsequent biliary excretion has been proposed as the underlying disease mechanism. However, liver-specific Zip14 KO mice exhibit decreased manganese only in the liver and do not develop manganese accumulation in other tissues under normal conditions. This suggests that impaired hepatobiliary excretion is not the primary cause for manganese overload observed in individuals lacking functional ZIP14. We therefore hypothesized that increased intestinal manganese absorption could induce manganese hyperaccumulation when ZIP14 is inactivated. To elucidate the role of ZIP14 in manganese absorption, here we used CaCo-2 Transwell cultures as a model system for intestinal epithelia. The generation of a ZIP14-deficient CaCo-2 cell line enabled the identification of ZIP14 as the major transporter mediating basolateral manganese uptake in enterocytes. Lack of ZIP14 severely impaired basolateral-to-apical (secretory) manganese transport and strongly enhanced manganese transport in the apical-to-basolateral (absorptive) direction. Mechanistic studies provided evidence that ZIP14 restricts manganese transport in the absorptive direction via direct basolateral reuptake of freshly absorbed manganese. In support of such function of intestinal ZIP14 in vivo, manganese levels in the livers and brains of intestine-specific Zip14 KO mice were significantly elevated. Our findings highlight the importance of intestinal ZIP14 in regulating systemic manganese homeostasis.en_US
dc.description.sponsorshipNational Institutes of Health [R00DK104066]en_US
dc.language.isoenen_US
dc.publisherAMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INCen_US
dc.rights© 2019 Scheiber et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.en_US
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/
dc.subjectCaCo-2en_US
dc.subjectSLC39A14en_US
dc.subjectZIP14en_US
dc.subjectabsorptionen_US
dc.subjecthomeostasisen_US
dc.subjectintestineen_US
dc.subjectmanganeseen_US
dc.subjectmetalen_US
dc.subjecttransporteren_US
dc.titleThe intestinal metal transporter ZIP14 maintains systemic manganese homeostasisen_US
dc.typeArticleen_US
dc.identifier.eissn1083-351X
dc.contributor.departmentUniv Arizona, Dept Nutr Scien_US
dc.identifier.journalJOURNAL OF BIOLOGICAL CHEMISTRYen_US
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en_US
dc.eprint.versionFinal accepted manuscripten_US
dc.source.journaltitleThe Journal of biological chemistry
refterms.dateFOA2019-07-25T21:59:44Z


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