Comprehensive Physiology Wiley Online Library
For Librarians For Authors Editors About

Zinc Transport in the Mammalian Intestine

Stephen R. Hennigar, James P. McClung

10.1002/cphy.c180001

Source: Volume 9, Issue 1, January 2019

Published online: December 2018

Full Article on Wiley Online Library



ABSTRACT

Zinc homeostasis is primarily maintained in the proximal small intestine. Sophisticated transport mechanisms maintain zinc homeostasis by controlling the uptake and efflux of zinc in intestinal absorptive epithelial cells. Zrt‐irt‐like proteins (ZIPs) and zinc transporters (ZnTs) function in a coordinated manner to assimilate zinc from the lumen of the small intestine, subcellular compartments within the absorptive epithelial cell, and circulation. This manuscript details zinc transport mechanisms in the mammalian small intestine, along with factors that regulate these processes and consequences of dysregulated zinc transport. © 2019 American Physiological Society. Compr Physiol 9:59‐74, 2019.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1. Relationship between zinc intake and zinc absorption. Zinc provided in aqueous solution or in a high (phytate:zinc molar ratio = 5‐7) or low (phytate:zinc molar ratio = 15‐23) bioavailable diet are shown. The amount of zinc absorbed depends on its bioavailability; zinc absorption plateaus with increased zinc intakes. Figure adapted, with permission, from (78,181).
Figure 2. Figure 2. Zinc transporter structure and function. Schematic diagram of (A) zrt‐irt‐like proteins (ZIPs) and (B) zinc transporters (ZnTs). Fourteen ZIPs and 10 ZnTs have been identified and are encoded by the SLC39A1‐14 and SLC30A1‐10 genes, respectively. The arrows indicate the direction of zinc transport. ZIPs are eight transmembrane proteins and function to import zinc into the cytosol, either from outside the cell or from an intracellular compartment. The majority of ZnTs are six transmembrane proteins and function to export zinc from the cytosol, either out of the cell or into an intracellular compartment. Both families homo‐ or heterodimerize to transport zinc.
Figure 3. Figure 3. Phylogenetic trees of the (A) zrt‐irt‐like protein (ZIP) and (B) zinc transporter (ZnT) families. UniProtKB/Swiss‐Prot protein sequences for human ZIP1‐14 and ZnT1‐10 were obtained from the National Center for Biotechnology Information (NCBI) protein database. Phylogenetic trees were generated using the European Molecular Biology Laboratory – European Bioinformatic Institute (EMBL‐EBI) Clustal Omega multiple sequence alignment program (49,162). The subfamily to which each transporter belongs is shown in parentheses.
Figure 4. Figure 4. Morphology of the mammalian small intestine and zinc transport in the enterocyte. The lining of the intestinal epithelium is composed of columnar absorptive enterocytes, mucous secreting goblet cells, and crypts of Lieberkühn. Enterocytes (inset) are a polarized cell type with distinct apical, lateral, and basolateral surfaces. The apical surface faces the intestinal lumen and is specialized for absorption with finger‐like microvilli projections that increase its surface area. The lateral and basolateral membranes contact adjacent cells and the basement membrane, respectively, and mediate the transport of nutrients into circulation. The inset shows zinc transport in the enterocyte in (A) zinc deficient and (B) zinc adequate or excess conditions. Zinc transporters with known intestinal localization are depicted. In response to low zinc conditions, ZIP4 translocates to the apical membrane and is primarily responsible for zinc uptake into the cell. In zinc adequate or excess conditions, paracellular zinc transport may override saturable zinc transport mechanisms. ZIP4 at the apical surface is rapidly endocytosed and degraded. Expression of intracellular metallothioneins and ZnT1 at the basolateral membrane increase to buffer the rise in labile zinc and export zinc from the cell, respectively. In contrast to low zinc conditions where ZIP5 is endocytosed and degraded, ZIP5 is localized to the basolateral surface in zinc adequate or excess conditions. ZnT2 and ZnT4 increase in response to zinc and transport zinc into secretory vesicles. ZnT5, ZnT6, and ZnT7 function to import zinc into the early secretory system and ZIP14 is found on the basolateral membrane; these transporters are generally refractory to the zinc status of the cell. ZnT5B is localized to the apical membrane and is capable of transporting zinc bidirectionally. EE, early endosome; LYS, lysosome; MT, metallothionein; SV, secretory vesicle; ZnT5B, ZnT5 variant B.


Figure 1. Relationship between zinc intake and zinc absorption. Zinc provided in aqueous solution or in a high (phytate:zinc molar ratio = 5‐7) or low (phytate:zinc molar ratio = 15‐23) bioavailable diet are shown. The amount of zinc absorbed depends on its bioavailability; zinc absorption plateaus with increased zinc intakes. Figure adapted, with permission, from (78,181).


Figure 2. Zinc transporter structure and function. Schematic diagram of (A) zrt‐irt‐like proteins (ZIPs) and (B) zinc transporters (ZnTs). Fourteen ZIPs and 10 ZnTs have been identified and are encoded by the SLC39A1‐14 and SLC30A1‐10 genes, respectively. The arrows indicate the direction of zinc transport. ZIPs are eight transmembrane proteins and function to import zinc into the cytosol, either from outside the cell or from an intracellular compartment. The majority of ZnTs are six transmembrane proteins and function to export zinc from the cytosol, either out of the cell or into an intracellular compartment. Both families homo‐ or heterodimerize to transport zinc.


Figure 3. Phylogenetic trees of the (A) zrt‐irt‐like protein (ZIP) and (B) zinc transporter (ZnT) families. UniProtKB/Swiss‐Prot protein sequences for human ZIP1‐14 and ZnT1‐10 were obtained from the National Center for Biotechnology Information (NCBI) protein database. Phylogenetic trees were generated using the European Molecular Biology Laboratory – European Bioinformatic Institute (EMBL‐EBI) Clustal Omega multiple sequence alignment program (49,162). The subfamily to which each transporter belongs is shown in parentheses.


Figure 4. Morphology of the mammalian small intestine and zinc transport in the enterocyte. The lining of the intestinal epithelium is composed of columnar absorptive enterocytes, mucous secreting goblet cells, and crypts of Lieberkühn. Enterocytes (inset) are a polarized cell type with distinct apical, lateral, and basolateral surfaces. The apical surface faces the intestinal lumen and is specialized for absorption with finger‐like microvilli projections that increase its surface area. The lateral and basolateral membranes contact adjacent cells and the basement membrane, respectively, and mediate the transport of nutrients into circulation. The inset shows zinc transport in the enterocyte in (A) zinc deficient and (B) zinc adequate or excess conditions. Zinc transporters with known intestinal localization are depicted. In response to low zinc conditions, ZIP4 translocates to the apical membrane and is primarily responsible for zinc uptake into the cell. In zinc adequate or excess conditions, paracellular zinc transport may override saturable zinc transport mechanisms. ZIP4 at the apical surface is rapidly endocytosed and degraded. Expression of intracellular metallothioneins and ZnT1 at the basolateral membrane increase to buffer the rise in labile zinc and export zinc from the cell, respectively. In contrast to low zinc conditions where ZIP5 is endocytosed and degraded, ZIP5 is localized to the basolateral surface in zinc adequate or excess conditions. ZnT2 and ZnT4 increase in response to zinc and transport zinc into secretory vesicles. ZnT5, ZnT6, and ZnT7 function to import zinc into the early secretory system and ZIP14 is found on the basolateral membrane; these transporters are generally refractory to the zinc status of the cell. ZnT5B is localized to the apical membrane and is capable of transporting zinc bidirectionally. EE, early endosome; LYS, lysosome; MT, metallothionein; SV, secretory vesicle; ZnT5B, ZnT5 variant B.
References
 1.Alam S, Hennigar SR, Gallagher C, Soybel DI, Kelleher SL. Exome sequencing of SLC30A2 identifies novel loss‐ and gain‐of‐function variants associated with breast cell dysfunction. J Mammary Gland Biol Neoplasia 20: 159‐172, 2015.
 2.Andreini C, Banci L, Bertini I, Rosato A. Counting the zinc‐proteins encoded in the human genome. J Proteome Res 5: 196‐201, 2006.
 3.Andrews GK, Wang H, Dey SK, Palmiter RD. Mouse zinc transporter 1 gene provides an essential function during early embryonic development. Genesis 40: 74‐81, 2004.
 4.Atherton DJ, Muller DP, Aggett PJ, Harries JT. A defect in zinc uptake by jejunal biopsies in acrodermatitis enteropathica. Clin Sci (Lond) 56: 505‐507, 1979.
 5.Azriel‐Tamir H, Sharir H, Schwartz B, Hershfinkel M. Extracellular zinc triggers ERK‐dependent activation of Na+/H+ exchange in colonocytes mediated by the zinc‐sensing receptor. J Biol Chem 279: 51804‐51816, 2004.
 6.Barnes PM, Moynahan EJ. Zinc deficiency in acrodermatitis enteropathica: Multiple dietary intolerance treated with synthetic diet. Proc R Soc Med 66: 327‐329, 1973.
 7.Beker Aydemir T, Chang SM, Guthrie GJ, Maki AB, Ryu MS, Karabiyik A, Cousins RJ. Zinc transporter ZIP14 functions in hepatic zinc, iron and glucose homeostasis during the innate immune response (endotoxemia). PLoS One 7: e48679, 2012.
 8.Bin BH, Fukada T, Hosaka T, Yamasaki S, Ohashi W, Hojyo S, Miyai T, Nishida K, Yokoyama S, Hirano T. Biochemical characterization of human ZIP13 protein: A homo‐dimerized zinc transporter involved in the spondylocheiro dysplastic Ehlers‐Danlos syndrome. J Biol Chem 286: 40255‐40265, 2011.
 9.Bosomworth HJ, Thornton JK, Coneyworth LJ, Ford D, Valentine RA. Efflux function, tissue‐specific expression and intracellular trafficking of the Zn transporter ZnT10 indicate roles in adult Zn homeostasis. Metallomics 4: 771‐779, 2012.
 10.Boyett JD, Sullivan JF. Distribution of protein‐bound zinc in normal and cirrhotic serum. Metabolism 19: 148‐157, 1970.
 11.Caggiano V, Schnitzler R, Strauss W, Baker RK, Carter AC, Josephson AS, Wallach S. Zinc deficiency in a patient with retarded growth, hypogonadism, hypogammaglobulinemia and chronic infection. Am J Med Sci 257: 305‐319, 1969.
 12.Chen YH, Kim JH, Stallcup MR. GAC63, a GRIP1‐dependent nuclear receptor coactivator. Mol Cell Biol 25: 5965‐5972, 2005.
 13.Chi ZH, Wang X, Wang ZY, Gao HL, Dahlstrom A, Huang L. Zinc transporter 7 is located in the cis‐Golgi apparatus of mouse choroid epithelial cells. Neuroreport 17: 1807‐1811, 2006.
 14.Chowanadisai W, Lonnerdal B, Kelleher SL. Identification of a mutation in SLC30A2 (ZnT‐2) in women with low milk zinc concentration that results in transient neonatal zinc deficiency. J Biol Chem 281: 39699‐39707, 2006.
 15.Claro da Silva T, Hiller C, Gai Z, Kullak‐Ublick GA. Vitamin D3 transactivates the zinc and manganese transporter SLC30A10 via the Vitamin D receptor. J Steroid Biochem Mol Biol 163: 77‐87, 2016.
 16.Clevers HC, Bevins CL. Paneth cells: Maestros of the small intestinal crypts. Annu Rev Physiol 75: 289‐311, 2013.
 17.Cohen L, Sekler I, Hershfinkel M. The zinc sensing receptor, ZnR/GPR39, controls proliferation and differentiation of colonocytes and thereby tight junction formation in the colon. Cell Death Dis 5: e1307, 2014.
 18.Coneyworth LJ, Jackson KA, Tyson J, Bosomworth HJ, van der Hagen E, Hann GM, Ogo OA, Swann DC, Mathers JC, Valentine RA, Ford D. Identification of the human zinc transcriptional regulatory element (ZTRE): A palindromic protein‐binding DNA sequence responsible for zinc‐induced transcriptional repression. J Biol Chem 287: 36567‐36581, 2012.
 19.Coppen DE, Davies NT. Studies on the effects of dietary zinc dose on 65 Zn absorption in vivo and on the effects of Zn status on 65 Zn absorption and body loss in young rats. Br J Nutr 57: 35‐44, 1987.
 20.Council NR. Recommended Dietary Allowances Washington, DC: National Academy of Sciences, 1974, p. 128.
 21.Coyle P, Philcox JC, Rofe AM. Metallothionein‐null mice absorb less Zn from an egg‐white diet, but a similar amount from solutions, although with altered intertissue Zn distribution. J Nutr 129: 372‐379, 1999.
 22.Cragg RA, Christie GR, Phillips SR, Russi RM, Küry S, Mathers JC, Taylor PM, Ford D. A novel zinc‐regulated human zinc transporter, hZTL1, is localized to the enterocyte apical membrane. J Biol Chem 277: 22789‐22797, 2002.
 23.Cragg RA, Phillips SR, Piper JM, Varma JS, Campbell FC, Mathers JC, Ford D. Homeostatic regulation of zinc transporters in the human small intestine by dietary zinc supplementation. Gut 54: 469‐478, 2005.
 24.Davies NT, Williams RB. The effect of pregnancy and lactation on the absorption of zinc and lysine by the rat duodenum in situ. Br J Nutr 38: 417‐423, 1977.
 25.Davis SR, McMahon RJ, Cousins RJ. Metallothionein knockout and transgenic mice exhibit altered intestinal processing of zinc with uniform zinc‐dependent zinc transporter‐1 expression. J Nutr 128: 825‐831, 1998.
 26.de Benoist B, Darnton‐Hill I, Davidsson L, Fontaine O, Hotz C. Conclusions of the joint WHO/UNICEF/IAEA/IZiNCG interagency meeting on zinc status indicators. Food Nutr Bull 28: S480‐S484, 2007.
 27.Dempski RE. The cation selectivity of the ZIP transporters. Curr Top Membr 69: 221‐245, 2012.
 28.Donangelo CM, Zapata CL, Woodhouse LR, Shames DM, Mukherjea R, King JC. Zinc absorption and kinetics during pregnancy and lactation in Brazilian women. Am J Clin Nutr 82: 118‐124, 2005.
 29.Dubi N, Gheber L, Fishman D, Sekler I, Hershfinkel M. Extracellular zinc and zinc‐citrate, acting through a putative zinc‐sensing receptor, regulate growth and survival of prostate cancer cells. Carcinogenesis 29: 1692‐1700, 2008.
 30.Dufner‐Beattie J, Huang ZL, Geiser J, Xu W, Andrews GK. Mouse ZIP1 and ZIP3 genes together are essential for adaptation to dietary zinc deficiency during pregnancy. Genesis 44: 239‐251, 2006.
 31.Dufner‐Beattie J, Kuo YM, Gitschier J, Andrews GK. The adaptive response to dietary zinc in mice involves the differential cellular localization and zinc regulation of the zinc transporters ZIP4 and ZIP5. J Biol Chem 279: 49082‐49090, 2004.
 32.Dufner‐Beattie J, Langmade SJ, Wang F, Eide D, Andrews GK. Structure, function, and regulation of a subfamily of mouse zinc transporter genes. J Biol Chem 278: 50142‐50150, 2003.
 33.Dufner‐Beattie J, Wang F, Kuo YM, Gitschier J, Eide D, Andrews GK. The acrodermatitis enteropathica gene ZIP4 encodes a tissue‐specific, zinc‐regulated zinc transporter in mice. J Biol Chem 278: 33474‐33481, 2003.
 34.Eide D, Broderius M, Fett J, Guerinot ML. A novel iron‐regulated metal transporter from plants identified by functional expression in yeast. Proc Natl Acad Sci U S A 93: 5624‐5628, 1996.
 35.Erway LC, Grider A, Jr. Zinc metabolism in lethal‐milk mice. Otolith, lactation, and aging effects. J Hered 75: 480‐484, 1984.
 36.Essatara MB, Levine AS, Morley JE, McClain CJ. Zinc deficiency and anorexia in rats: Normal feeding patterns and stress induced feeding. Physiol Behav 32: 469‐474, 1984.
 37.Evans GW, Grace CI, Votava HJ. A proposed mechanism of zinc absorption in the rat. Am J Physiol 228: 501‐505, 1975.
 38.Fagerberg L, Hallstrom BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J, Habuka M, Tahmasebpoor S, Danielsson A, Edlund K, Asplund A, Sjostedt E, Lundberg E, Szigyarto CA, Skogs M, Takanen JO, Berling H, Tegel H, Mulder J, Nilsson P, Schwenk JM, Lindskog C, Danielsson F, Mardinoglu A, Sivertsson A, von Feilitzen K, Forsberg M, Zwahlen M, Olsson I, Navani S, Huss M, Nielsen J, Ponten F, Uhlen M. Analysis of the human tissue‐specific expression by genome‐wide integration of transcriptomics and antibody‐based proteomics. Mol Cell Proteomics 13: 397‐406, 2014.
 39.Finley JW, Johnson PE, Reeves PG, Vanderpool RA, Briske‐Anderson M. Effect of bile/pancreatic secretions on absorption of radioactive or stable zinc. In vivo and in vitro studies. Biol Trace Elem Res 42: 81‐96, 1994.
 40.Fukunaka A, Suzuki T, Kurokawa Y, Yamazaki T, Fujiwara N, Ishihara K, Migaki H, Okumura K, Masuda S, Yamaguchi‐Iwai Y, Nagao M, Kambe T. Demonstration and characterization of the heterodimerization of ZnT5 and ZnT6 in the early secretory pathway. J Biol Chem 284: 30798‐30806, 2009.
 41.Gaetke LM, McClain CJ, Talwalkar RT, Shedlofsky SI. Effects of endotoxin on zinc metabolism in human volunteers. Am J Physiol 272: E952‐E956, 1997.
 42.Gaither LA, Eide DJ. Eukaryotic zinc transporters and their regulation. Biometals 14: 251‐270, 2001.
 43.Gaither LA, Eide DJ. The human ZIP1 transporter mediates zinc uptake in human K562 erythroleukemia cells. J Biol Chem 276: 22258‐22264, 2001.
 44.Gaither LA, Eide DJ. Functional expression of the human hZIP2 zinc transporter. J Biol Chem 275: 5560‐5564, 2000.
 45.Ganz T, Nemeth E. Hepcidin and iron homeostasis. Biochim Biophys Acta 1823: 1434‐1443, 2012.
 46.Geiser J, De Lisle RC, Andrews GK. The zinc transporter Zip5 (Slc39a5) regulates intestinal zinc excretion and protects the pancreas against zinc toxicity. PLoS One 8: e82149, 2013.
 47.Glover CN, Hogstrand C. Effects of dissolved metals and other hydrominerals on in vivo intestinal zinc uptake in freshwater rainbow trout. Aquat Toxicol 62: 281‐293, 2003.
 48.Golan Y, Berman B, Assaraf YG. Heterodimerization, altered subcellular localization, and function of multiple zinc transporters in viable cells using bimolecular fluorescence complementation. J Biol Chem 290: 9050‐9063, 2015.
 49.Goujon M, McWilliam H, Li W, Valentin F, Squizzato S, Paern J, Lopez R. A new bioinformatics analysis tools framework at EMBL‐EBI. Nucleic Acids Res 38: W695‐W699, 2010.
 50.Grider A, Bakre AA, Laing EM, Lewis RD. In silico analysis of microRNA regulation of bone development: Metal responsive element‐binding transcription factor 1 and bone signaling pathways. Austin J Nutr Metab 4: 1042, 2017.
 51.Grider A, Jr., Erway LC. Intestinal metallothionein in lethal‐milk mice with systemic zinc deficiency. Biochem Genet 24: 635‐642, 1986.
 52.Grider A, Mouat MF. The acrodermatitis enteropathica mutation affects protein expression in human fibroblasts: Analysis by two‐dimensional gel electrophoresis. J Nutr 128: 1311‐1314, 1998.
 53.Guerinot ML. The ZIP family of metal transporters. Biochim Biophys Acta 1465: 190‐198, 2000.
 54.Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, Boron WF, Nussberger S, Gollan JL, Hediger MA. Cloning and characterization of a mammalian proton‐coupled metal‐ion transporter. Nature 388: 482‐488, 1997.
 55.Guo L, Lichten LA, Ryu MS, Liuzzi JP, Wang F, Cousins RJ. STAT5‐glucocorticoid receptor interaction and MTF‐1 regulate the expression of ZnT2 (Slc30a2) in pancreatic acinar cells. Proc Natl Acad Sci U S A 107: 2818‐2823, 2010.
 56.Guthrie GJ, Aydemir TB, Troche C, Martin AB, Chang SM, Cousins RJ. Influence of ZIP14 (slc39A14) on intestinal zinc processing and barrier function. Am J Physiol Gastrointest Liver Physiol 308: G171‐G178, 2015.
 57.Hambidge KM, Hambidge C, Jacobs M, Baum JD. Low levels of zinc in hair, anorexia, poor growth, and hypogeusia in children. Pediatr Res 6: 868‐874, 1972.
 58.Hambidge KM, Huffer JW, Raboy V, Grunwald GK, Westcott JL, Sian L, Miller LV, Dorsch JA, Krebs NF. Zinc absorption from low‐phytate hybrids of maize and their wild‐type isohybrids. Am J Clin Nutr 79: 1053‐1059, 2004.
 59.Hambidge KM, Miller LV, Mazariegos M, Westcott J, Solomons NW, Raboy V, Kemp JF, Das A, Goco N, Hartwell T, Wright L, Krebs NF. Upregulation of zinc absorption matches increases in physiologic requirements for zinc in women consuming high‐ or moderate‐phytate diets during late pregnancy and early lactation. J Nutr 147: 1079‐1085, 2017.
 60.Hambidge M, Krebs NF. Interrelationships of key variables of human zinc homeostasis: Relevance to dietary zinc requirements. Annu Rev Nutr 21: 429‐452, 2001.
 61.Hara H, Konishi A, Kasai T. Contribution of the cecum and colon to zinc absorption in rats. J Nutr 130: 83‐89, 2000.
 62.Hediger MA, Romero MF, Peng JB, Rolfs A, Takanaga H, Bruford EA. The ABCs of solute carriers: Physiological, pathological and therapeutic implications of human membrane transport proteinsIntroduction. Pflugers Arch 447: 465‐468, 2004.
 63.Hennigar SR, Kelleher SL. Zinc networks: The cell‐specific compartmentalization of zinc for specialized functions. Biol Chem 393: 565‐578, 2012.
 64.Hennigar SR, Kelley AM, McClung JP. Metallothionein and zinc transporter expression in circulating human blood Cells as biomarkers of zinc status: A systematic review. Adv Nutr 7: 735‐746, 2016.
 65.Hennigar SR, McClung JP. Hepcidin attenuates zinc efflux in Caco‐2 cells. J Nutr 146: 2167‐2173, 2016.
 66.Hennigar SR, McClung JP. Homeostatic regulation of trace mineral transport by ubiquitination of membrane transporters. Nutr Rev 74: 59‐67, 2016.
 67.Hershfinkel M, Moran A, Grossman N, Sekler I. A zinc‐sensing receptor triggers the release of intracellular Ca2+ and regulates ion transport. Proc Natl Acad Sci U S A 98: 11749‐11754, 2001.
 68.Hinskens B, Philcox JC, Coyle P, Rofe AM. Increased zinc absorption but not secretion in the small intestine of metallothionein‐null mice. Biol Trace Elem Res 78: 231‐240, 2000.
 69.Hoadley JE, Leinart AS, Cousins RJ. Kinetic analysis of zinc uptake and serosal transfer by vascularly perfused rat intestine. Am J Physiol 252: G825‐G831, 1987.
 70.Hotz C, Peerson JM, Brown KH. Suggested lower cutoffs of serum zinc concentrations for assessing zinc status: Reanalysis of the second National Health and Nutrition Examination Survey data (1976‐1980). Am J Clin Nutr 78: 756‐764, 2003.
 71.Huang D, Zhuo Z, Fang S, Yue M, Feng J. Different zinc sources have diverse impacts on gene expression of zinc absorption related transporters in intestinal porcine epithelial cells. Biol Trace Elem Res 173: 325‐332, 2016.
 72.Huang L, Gitschier J. A novel gene involved in zinc transport is deficient in the lethal milk mouse. Nat Genet 17: 292‐297, 1997.
 73.Huang L, Kirschke CP, Gitschier J. Functional characterization of a novel mammalian zinc transporter, ZnT6. J Biol Chem 277: 26389‐26395, 2002.
 74.Huang L, Kirschke CP, Zhang Y, Yu YY. The ZIP7 gene (Slc39a7) encodes a zinc transporter involved in zinc homeostasis of the Golgi apparatus. J Biol Chem 280: 15456‐15463, 2005.
 75.Huang L, Tepaamorndech S. The SLC30 family of zinc transporters ‐ a review of current understanding of their biological and pathophysiological roles. Mol Aspects Med 34: 548‐560, 2013.
 76.Huang L, Yu YY, Kirschke CP, Gertz ER, Lloyd KK. Znt7 (Slc30a7)‐deficient mice display reduced body zinc status and body fat accumulation. J Biol Chem 282: 37053‐37063, 2007.
 77.Huang ZL, Dufner‐Beattie J, Andrews GK. Expression and regulation of SLC39A family zinc transporters in the developing mouse intestine. Dev Biol 295: 571‐579, 2006.
 78.Hunt JR, Beiseigel JM, Johnson LK. Adaptation in human zinc absorption as influenced by dietary zinc and bioavailability. Am J Clin Nutr 87: 1336‐1345, 2008.
 79.Inoue K, Matsuda K, Itoh M, Kawaguchi H, Tomoike H, Aoyagi T, Nagai R, Hori M, Nakamura Y, Tanaka T. Osteopenia and male‐specific sudden cardiac death in mice lacking a zinc transporter gene, Znt5. Hum Mol Genet 11: 1775‐1784, 2002.
 80.Iqbal TH, Lewis KO, Cooper BT. Phytase activity in the human and rat small intestine. Gut 35: 1233‐1236, 1994.
 81.Jackson KA, Helston RM, McKay JA, O'Neill ED, Mathers JC, Ford D. Splice variants of the human zinc transporter ZnT5 (SLC30A5) are differentially localized and regulated by zinc through transcription and mRNA stability. J Biol Chem 282: 10423‐10431, 2007.
 82.Jackson MJ. Physiology of zinc: General aspects. In: Zinc in human biology, edited by Mills CF. London: Springer, 1989, pp. 1‐14.
 83.Jeong J, Eide DJ. The SLC39 family of zinc transporters. Mol Aspects Med 34: 612‐619, 2013.
 84.Johnson PE, Hunt CD, Milne DB, Mullen LK. Homeostatic control of zinc metabolism in men: Zinc excretion and balance in men fed diets low in zinc. Am J Clin Nutr 57: 557‐565, 1993.
 85.Jou MY, Hall AG, Philipps AF, Kelleher SL, Lonnerdal B. Tissue‐specific alterations in zinc transporter expression in intestine and liver reflect a threshold for homeostatic compensation during dietary zinc deficiency in weanling rats. J Nutr 139: 835‐841, 2009.
 86.Jou MY, Philipps AF, Kelleher SL, Lonnerdal B. Effects of zinc exposure on zinc transporter expression in human intestinal cells of varying maturity. J Pediatr Gastroenterol Nutr 50: 587‐595, 2010.
 87.Kagi JH, Schaffer A. Biochemistry of metallothionein. Biochemistry 27: 8509‐8515, 1988.
 88.Kaler P, Prasad R. Molecular cloning and functional characterization of novel zinc transporter rZip10 (Slc39a10) involved in zinc uptake across rat renal brush‐border membrane. Am J Physiol Renal Physiol 292: F217‐F229, 2007.
 89.Kambe T, Andrews GK. Novel proteolytic processing of the ectodomain of the zinc transporter ZIP4 (SLC39A4) during zinc deficiency is inhibited by acrodermatitis enteropathica mutations. Mol Cell Biol 29: 129‐139, 2009.
 90.Kambe T, Narita H, Yamaguchi‐Iwai Y, Hirose J, Amano T, Sugiura N, Sasaki R, Mori K, Iwanaga T, Nagao M. Cloning and characterization of a novel mammalian zinc transporter, zinc transporter 5, abundantly expressed in pancreatic beta cells. J Biol Chem 277: 19049‐19055, 2002.
 91.Khan FR, McGeer JC. Zn‐stimulated mucus secretion in the rainbow trout (Oncorhynchus mykiss) intestine inhibits Cd accumulation and Cd‐induced lipid peroxidation. Aquat Toxicol 142‐143: 17‐25, 2013.
 92.Khoury GA, Baliban RC, Floudas CA. Proteome‐wide post‐translational modification statistics: Frequency analysis and curation of the swiss‐prot database. Sci Rep 1: 90, 2011.
 93.Kim BE, Wang F, Dufner‐Beattie J, Andrews GK, Eide DJ, Petris MJ. Zn2+‐stimulated endocytosis of the mZIP4 zinc transporter regulates its location at the plasma membrane. J Biol Chem 279: 4523‐4530, 2004.
 94.King JC. Assessment of zinc status. J Nutr 120(Suppl 11): 1474‐1479, 1990.
 95.King JC, Brown KH, Gibson RS, Krebs NF, Lowe NM, Siekmann JH, Raiten DJ. Biomarkers of nutrition for development (BOND)‐zinc review. J Nutr 146: 858S‐885S, 2016.
 96.Kirschke CP, Huang L. ZnT7, a novel mammalian zinc transporter, accumulates zinc in the Golgi apparatus. J Biol Chem 278: 4096‐4102, 2003.
 97.Klasing KC. Effect of inflammatory agents and interleukin 1 on iron and zinc metabolism. Am J Physiol 247: R901‐R904, 1984.
 98.Koch S, Capaldo CT, Hilgarth RS, Fournier B, Parkos CA, Nusrat A. Protein kinase CK2 is a critical regulator of epithelial homeostasis in chronic intestinal inflammation. Mucosal Immunol 6: 136‐145, 2013.
 99.Krezel A, Maret W. Zinc‐buffering capacity of a eukaryotic cell at physiological pZn. J Biol Inorg Chem 11: 1049‐1062, 2006.
 100.Kury S, Dreno B, Bezieau S, Giraudet S, Kharfi M, Kamoun R, Moisan JP. Identification of SLC39A4, a gene involved in acrodermatitis enteropathica. Nat Genet 31: 239‐240, 2002.
 101.Laity JH, Andrews GK. Understanding the mechanisms of zinc‐sensing by metal‐response element binding transcription factor‐1 (MTF‐1). Arch Biochem Biophys 463: 201‐210, 2007.
 102.Langmade SJ, Ravindra R, Daniels PJ, Andrews GK. The transcription factor MTF‐1 mediates metal regulation of the mouse ZnT1 gene. J Biol Chem 275: 34803‐34809, 2000.
 103.Laukens D, Waeytens A, De Bleser P, Cuvelier C, De Vos M. Human metallothionein expression under normal and pathological conditions: Mechanisms of gene regulation based on in silico promoter analysis. Crit Rev Eukaryot Gene Expr 19: 301‐317, 2009.
 104.Lee HH, Prasad AS, Brewer GJ, Owyang C. Zinc absorption in human small intestine. Am J Physiol 256: G87‐G91, 1989.
 105.Lee J, Li Z, Brower‐Sinning R, John B. Regulatory circuit of human microRNA biogenesis. PLoS Comput Biol 3: e67, 2007.
 106.Lichten LA, Liuzzi JP, Cousins RJ. Interleukin‐1beta contributes via nitric oxide to the upregulation and functional activity of the zinc transporter Zip14 (Slc39a14) in murine hepatocytes. Am J Physiol Gastrointest Liver Physiol 296: G860‐G867, 2009.
 107.Lichten LA, Ryu MS, Guo L, Embury J, Cousins RJ. MTF‐1‐mediated repression of the zinc transporter Zip10 is alleviated by zinc restriction. PLoS One 6: e21526, 2011.
 108.Lichtlen P, Wang Y, Belser T, Georgiev O, Certa U, Sack R, Schaffner W. Target gene search for the metal‐responsive transcription factor MTF‐1. Nucleic Acids Res 29: 1514‐1523, 2001.
 109.Lin W, Chai J, Love J, Fu D. Selective electrodiffusion of zinc ions in a Zrt‐, Irt‐like protein, ZIPB. J Biol Chem 285: 39013‐39020, 2010.
 110.Lindenmayer GW, Stoltzfus RJ, Prendergast AJ. Interactions between zinc deficiency and environmental enteropathy in developing countries. Adv Nutr 5: 1‐6, 2014.
 111.Lioumi M, Ferguson CA, Sharpe PT, Freeman T, Marenholz I, Mischke D, Heizmann C, Ragoussis J. Isolation and characterization of human and mouse ZIRTL, a member of the IRT1 family of transporters, mapping within the epidermal differentiation complex. Genomics 62: 272‐280, 1999.
 112.Liu B, Qian SB. Translational regulation in nutrigenomics. Adv Nutr 2: 511‐519, 2011.
 113.Liu Z, Li H, Soleimani M, Girijashanker K, Reed JM, He L, Dalton TP, Nebert DW. Cd2+ versus Zn2+ uptake by the ZIP8 HCO3–dependent symporter: Kinetics, electrogenicity and trafficking. Biochem Biophys Res Commun 365: 814‐820, 2008.
 114.Liuzzi JP, Blanchard RK, Cousins RJ. Differential regulation of zinc transporter 1, 2, and 4 mRNA expression by dietary zinc in rats. J Nutr 131: 46‐52, 2001.
 115.Liuzzi JP, Bobo JA, Cui L, McMahon RJ, Cousins RJ. Zinc transporters 1, 2 and 4 are differentially expressed and localized in rats during pregnancy and lactation. J Nutr 133: 342‐351, 2003.
 116.Liuzzi JP, Bobo JA, Lichten LA, Samuelson DA, Cousins RJ. Responsive transporter genes within the murine intestinal‐pancreatic axis form a basis of zinc homeostasis. Proc Natl Acad Sci U S A 101: 14355‐14360, 2004.
 117.Liuzzi JP, Guo L, Chang SM, Cousins RJ. Kruppel‐like factor 4 regulates adaptive expression of the zinc transporter Zip4 in mouse small intestine. Am J Physiol Gastrointest Liver Physiol 296: G517‐G523, 2009.
 118.Liuzzi JP, Lichten LA, Rivera S, Blanchard RK, Aydemir TB, Knutson MD, Ganz T, Cousins RJ. Interleukin‐6 regulates the zinc transporter Zip14 in liver and contributes to the hypozincemia of the acute‐phase response. Proc Natl Acad Sci U S A 102: 6843‐6848, 2005.
 119.Lombeck T, Schnippering HG, Ritzl F, Feinendegen LE, Bremer HJ. Letter: Absorption of zinc in acrodermatitis enteropathica. Lancet 1: 855, 1975.
 120.Lonnerdal B. Dietary factors influencing zinc absorption. J Nutr 130: 1378S‐1383S, 2000.
 121.Lonnerdal B, Schneeman BO, Keen CL, Hurley LS. Molecular distribution of zinc in biliary and pancreatic secretions. Biol Trace Elem Res 2: 149‐158, 1980.
 122.Lowe NM. Assessing zinc in humans. Curr Opin Clin Nutr Metab Care 19: 321‐327, 2016.
 123.Mao X, Kim BE, Wang F, Eide DJ, Petris MJ. A histidine‐rich cluster mediates the ubiquitination and degradation of the human zinc transporter, hZIP4, and protects against zinc cytotoxicity. J Biol Chem 282: 6992‐7000, 2007.
 124.Martin AB, Aydemir TB, Guthrie GJ, Samuelson DA, Chang SM, Cousins RJ. Gastric and colonic zinc transporter ZIP11 (Slc39a11) in mice responds to dietary zinc and exhibits nuclear localization. J Nutr 143: 1882‐1888, 2013.
 125.Matsuura W, Yamazaki T, Yamaguchi‐Iwai Y, Masuda S, Nagao M, Andrews GK, Kambe T. SLC39A9 (ZIP9) regulates zinc homeostasis in the secretory pathway: Characterization of the ZIP subfamily I protein in vertebrate cells. Biosci Biotechnol Biochem 73: 1142‐1148, 2009.
 126.McCormick NH, Kelleher SL. ZnT4 provides zinc to zinc‐dependent proteins in the trans‐Golgi network critical for cell function and Zn export in mammary epithelial cells. Am J Physiol Cell Physiol 303: C291‐C297, 2012.
 127.McDevitt CA, Ogunniyi AD, Valkov E, Lawrence MC, Kobe B, McEwan AG, Paton JC. A molecular mechanism for bacterial susceptibility to zinc. PLoS Pathog 7: e1002357, 2011.
 128.McMahon RJ, Cousins RJ. Regulation of the zinc transporter ZnT‐1 by dietary zinc. Proc Natl Acad Sci U S A 95: 4841‐4846, 1998.
 129.Methfessel AH, Spencer H. Zinc metabolism in the rat. I. Intestinal absorption of zinc. J Appl Physiol 34: 58‐62, 1973.
 130.Michalczyk AA, Ackland ML. hZip1 (hSLC39A1) regulates zinc homoeostasis in gut epithelial cells. Genes Nutr 8: 475‐486, 2013.
 131.Moechars D, Depoortere I, Moreaux B, de Smet B, Goris I, Hoskens L, Daneels G, Kass S, Ver Donck L, Peeters T, Coulie B. Altered gastrointestinal and metabolic function in the GPR39‐obestatin receptor‐knockout mouse. Gastroenterology 131: 1131‐1141, 2006.
 132.Moleirinho A, Carneiro J, Matthiesen R, Silva RM, Amorim A, Azevedo L. Gains, losses and changes of function after gene duplication: Study of the metallothionein family. PLoS One 6: e18487, 2011.
 133.Moynahan EJ. Letter: Acrodermatitis enteropathica: A lethal inherited human zinc‐deficiency disorder. Lancet 2: 399‐400, 1974.
 134.Muga SJ, Grider A. Partial characterization of a human zinc‐deficiency syndrome by differential display. Biol Trace Elem Res 68: 1‐12, 1999.
 135.Murgia C, Vespignani I, Cerase J, Nobili F, Perozzi G. Cloning, expression, and vesicular localization of zinc transporter Dri 27/ZnT4 in intestinal tissue and cells. Am J Physiol 277: G1231‐G1239, 1999.
 136.Murgia C, Vespignani I, Rami R, Perozzi G. The Znt4 mutation in lethal milk mice affects intestinal zinc homeostasis through the expression of other Zn transporters. Genes Nutr 1: 61‐70, 2006.
 137.Naveh Y, Lee‐Ambrose LM, Samuelson DA, Cousins RJ. Malabsorption of zinc in rats with acetic acid‐induced enteritis and colitis. J Nutr 123: 1389‐1395, 1993.
 138.Ogo OA, Tyson J, Cockell SJ, Howard A, Valentine RA, Ford D. The zinc finger protein ZNF658 regulates the transcription of genes involved in zinc homeostasis and affects ribosome biogenesis through the zinc transcriptional regulatory element. Mol Cell Biol 35: 977‐987, 2015.
 139.Ohana E, Hoch E, Keasar C, Kambe T, Yifrach O, Hershfinkel M, Sekler I. Identification of the Zn2+ binding site and mode of operation of a mammalian Zn2+ transporter. J Biol Chem 284: 17677‐17686, 2009.
 140.Ohashi W, Kimura S, Iwanaga T, Furusawa Y, Irie T, Izumi H, Watanabe T, Hijikata A, Hara T, Ohara O, Koseki H, Sato T, Robine S, Mori H, Hattori Y, Watarai H, Mishima K, Ohno H, Hase K, Fukada T. Zinc transporter SLC39A7/ZIP7 promotes intestinal epithelial self‐renewal by resolving ER stress. PLoS Genet 12: e1006349, 2016.
 141.Outten CE, O'Halloran TV. Femtomolar sensitivity of metalloregulatory proteins controlling zinc homeostasis. Science 292: 2488‐2492, 2001.
 142.Palmiter RD, Cole TB, Findley SD. ZnT‐2, a mammalian protein that confers resistance to zinc by facilitating vesicular sequestration. EMBO J 15: 1784‐1791, 1996.
 143.Palmiter RD, Findley SD. Cloning and functional characterization of a mammalian zinc transporter that confers resistance to zinc. EMBO J 14: 639‐649, 1995.
 144.Pawan K, Neeraj S, Sandeep K, Kanta Ratho R, Rajendra P. Upregulation of Slc39a10 gene expression in response to thyroid hormones in intestine and kidney. Biochim Biophys Acta 1769: 117‐123, 2007.
 145.Piletz JA, Ganschow RE. Lethal milk mutation results in dietary zinc deficiency in nursing mice. Am J Clin Nutr 31: 560‐562, 1978.
 146.Piletz JE, Ganschow RE. Zinc deficiency in murine milk underlies expression of the lethal milk (lm) mutation. Science 199: 181‐183, 1978.
 147.Podany AB, Wright J, Lamendella R, Soybel DI, Kelleher SL. ZnT2‐mediated zinc import into Paneth cell granules is necessary for coordinated secretion and Paneth cell function in mice. Cell Mol Gastroenterol Hepatol 2: 369‐383, 2016.
 148.Powell JJ, Jugdaohsingh R, Thompson RP. The regulation of mineral absorption in the gastrointestinal tract. Proc Nutr Soc 58: 147‐153, 1999.
 149.Prasad AS, Halsted JA, Nadimi M. Syndrome of iron deficiency anemia, hepatosplenomegaly, hypogonadism, dwarfism and geophagia. Am J Med 31: 532‐546, 1961.
 150.Prasad AS, Oberleas D. Binding of zinc to amino acids and serum proteins in vitro. J Lab Clin Med 76: 416‐425, 1970.
 151.Prasad AS, Rabbani P, Abbasii A, Bowersox E, Fox MR. Experimental zinc deficiency in humans. Ann Intern Med 89: 483‐490, 1978.
 152.Qin Y, Dittmer PJ, Park JG, Jansen KB, Palmer AE. Measuring steady‐state and dynamic endoplasmic reticulum and Golgi Zn2+ with genetically encoded sensors. Proc Natl Acad Sci U S A 108: 7351‐7356, 2011.
 153.Ruz M, Carrasco F, Rojas P, Codoceo J, Inostroza J, Basfi‐fer K, Csendes A, Papapietro K, Pizarro F, Olivares M, Sian L, Westcott JL, Miller LV, Hambidge KM, Krebs NF. Zinc absorption and zinc status are reduced after Roux‐en‐Y gastric bypass: A randomized study using 2 supplements. Am J Clin Nutr 94: 1004‐1011, 2011.
 154.Salazar G, Falcon‐Perez JM, Harrison R, Faundez V. SLC30A3 (ZnT3) oligomerization by dityrosine bonds regulates its subcellular localization and metal transport capacity. PLoS One 4: e5896, 2009.
 155.Sandstead HH. Copper bioavailability and requirements. Am J Clin Nutr 35: 809‐814, 1982.
 156.Sandstead HH. Is zinc deficiency a public health problem? Nutrition 11: 87‐92, 1995.
 157.Sandstead HH, Prasad AS, Schulert AR, Farid Z, Miale A, Jr., Bassilly S, Darby WJ. Human zinc deficiency, endocrine manifestations and response to treatment. Am J Clin Nutr 20: 422‐442, 1967.
 158.Sandstrom B, Arvidsson B, Cederblad A, Bjorn‐Rasmussen E. Zinc absorption from composite meals. I. The significance of wheat extraction rate, zinc, calcium, and protein content in meals based on bread. Am J Clin Nutr 33: 739‐745, 1980.
 159.Sandstrom B, Davidsson L, Cederblad A, Lonnerdal B. Oral iron, dietary ligands and zinc absorption. J Nutr 115: 411‐414, 1985.
 160.Schweiger M, Steffl M, Amselgruber WM. Co‐localization of the zinc transporter ZnT8 (slc30A8) with ghrelin and motilin in the gastrointestinal tract of pigs. Histol Histopathol 31: 205‐211, 2016.
 161.Shusterman E, Beharier O, Shiri L, Zarivach R, Etzion Y, Campbell CR, Lee IH, Okabayashi K, Dinudom A, Cook DI, Katz A, Moran A. ZnT‐1 extrudes zinc from mammalian cells functioning as a Zn(2+)/H(+) exchanger. Metallomics 6: 1656‐1663, 2014.
 162.Sievers F, Wilm A, Dineen D, Gibson TJ, Karplus K, Li W, Lopez R, McWilliam H, Remmert M, Soding J, Thompson JD, Higgins DG. Fast, scalable generation of high‐quality protein multiple sequence alignments using Clustal Omega. Mol Syst Biol 7: 539, 2011.
 163.Sim DL, Chow VT. The novel human HUEL (C4orf1) gene maps to chromosome 4p12‐p13 and encodes a nuclear protein containing the nuclear receptor interaction motif. Genomics 59: 224‐233, 1999.
 164.Smith KT, Failla ML, Cousins RJ. Identification of albumin as the plasma carrier for zinc absorption by perfused rat intestine. Biochem J 184: 627‐633, 1979.
 165.Solomons NW, Jacob RA, Pineda O, Viteri F. Studies on the bioavailability of zinc in man. II. Absorption of zinc from organic and inorganic sources. J Lab Clin Med 94: 335‐343, 1979.
 166.Sonenberg N, Hinnebusch AG. Regulation of translation initiation in eukaryotes: Mechanisms and biological targets. Cell 136: 731‐745, 2009.
 167.Song Y, Leonard SW, Traber MG, Ho E. Zinc deficiency affects DNA damage, oxidative stress, antioxidant defenses, and DNA repair in rats. J Nutr 139: 1626‐1631, 2009.
 168.Steinhardt HJ, Adibi SA. Interaction between transport of zinc and other solutes in human intestine. Am J Physiol 247: G176‐G182, 1984.
 169.Sunuwar L, Gilad D, Hershfinkel M. The zinc sensing receptor, ZnR/GPR39, in health and disease. Front Biosci (Landmark Ed) 22: 1469‐1492, 2017.
 170.Sunuwar L, Medini M, Cohen L, Sekler I, Hershfinkel M. The zinc sensing receptor, ZnR/GPR39, triggers metabotropic calcium signalling in colonocytes and regulates occludin recovery in experimental colitis. Philos Trans R Soc Lond B Biol Sci 371(1700): 2016.
 171.Suzuki T, Ishihara K, Migaki H, Matsuura W, Kohda A, Okumura K, Nagao M, Yamaguchi‐Iwai Y, Kambe T. Zinc transporters, ZnT5 and ZnT7, are required for the activation of alkaline phosphatases, zinc‐requiring enzymes that are glycosylphosphatidylinositol‐anchored to the cytoplasmic membrane. J Biol Chem 280: 637‐643, 2005.
 172.Suzuki T, Ishihara K, Migaki H, Nagao M, Yamaguchi‐Iwai Y, Kambe T. Two different zinc transport complexes of cation diffusion facilitator proteins localized in the secretory pathway operate to activate alkaline phosphatases in vertebrate cells. J Biol Chem 280: 30956‐30962, 2005.
 173.Tandy S, Williams M, Leggett A, Lopez‐Jimenez M, Dedes M, Ramesh B, Srai SK, Sharp P. Nramp2 expression is associated with pH‐dependent iron uptake across the apical membrane of human intestinal Caco‐2 cells. J Biol Chem 275: 1023‐1029, 2000.
 174.Taniguchi M, Fukunaka A, Hagihara M, Watanabe K, Kamino S, Kambe T, Enomoto S, Hiromura M. Essential role of the zinc transporter ZIP9/SLC39A9 in regulating the activations of Akt and Erk in B‐cell receptor signaling pathway in DT40 cells. PLoS One 8: e58022, 2013.
 175.Taylor KM, Hiscox S, Nicholson RI, Hogstrand C, Kille P. Protein kinase CK2 triggers cytosolic zinc signaling pathways by phosphorylation of zinc channel ZIP7. Sci Signal 5: ra11, 2012.
 176.Taylor KM, Morgan HE, Johnson A, Nicholson RI. Structure‐function analysis of a novel member of the LIV‐1 subfamily of zinc transporters, ZIP14. FEBS Lett 579: 427‐432, 2005.
 177.Taylor KM, Morgan HE, Johnson A, Nicholson RI. Structure‐function analysis of HKE4, a member of the new LIV‐1 subfamily of zinc transporters. Biochem J 377: 131‐139, 2004.
 178.Taylor KM, Morgan HE, Smart K, Zahari NM, Pumford S, Ellis IO, Robertson JF, Nicholson RI. The emerging role of the LIV‐1 subfamily of zinc transporters in breast cancer. Mol Med 13: 396‐406, 2007.
 179.Taylor KM, Nicholson RI. The LZT proteins; the LIV‐1 subfamily of zinc transporters. Biochim Biophys Acta 1611: 16‐30, 2003.
 180.Thornton JK, Taylor KM, Ford D, Valentine RA. Differential subcellular localization of the splice variants of the zinc transporter ZnT5 is dictated by the different C‐terminal regions. PLoS One 6: e23878, 2011.
 181.Tran CD, Miller LV, Krebs NF, Lei S, Hambidge KM. Zinc absorption as a function of the dose of zinc sulfate in aqueous solution. Am J Clin Nutr 80: 1570‐1573, 2004.
 182.Turnlund JR, King JC, Keyes WR, Gong B, Michel MC. A stable isotope study of zinc absorption in young men: Effects of phytate and alpha‐cellulose. Am J Clin Nutr 40: 1071‐1077, 1984.
 183.Valentine RA, Jackson KA, Christie GR, Mathers JC, Taylor PM, Ford D. ZnT5 variant B is a bidirectional zinc transporter and mediates zinc uptake in human intestinal Caco‐2 cells. J Biol Chem 282: 14389‐14393, 2007.
 184.Vancampen DR, Mitchell EA. Absorption of Cu‐64, Zn‐65, Mo‐99, and Fe‐59 from ligated segments of the rat gastrointestinal tract. J Nutr 86: 120‐124, 1965.
 185.Vinkenborg JL, Nicolson TJ, Bellomo EA, Koay MS, Rutter GA, Merkx M. Genetically encoded FRET sensors to monitor intracellular Zn2+ homeostasis. Nat Methods 6: 737‐740, 2009.
 186.Wang F, Kim BE, Dufner‐Beattie J, Petris MJ, Andrews G, Eide DJ. Acrodermatitis enteropathica mutations affect transport activity, localization and zinc‐responsive trafficking of the mouse ZIP4 zinc transporter. Hum Mol Genet 13: 563‐571, 2004.
 187.Wang F, Kim BE, Petris MJ, Eide DJ. The mammalian Zip5 protein is a zinc transporter that localizes to the basolateral surface of polarized cells. J Biol Chem 279: 51433‐51441, 2004.
 188.Wang K, Pugh EW, Griffen S, Doheny KF, Mostafa WZ, al‐Aboosi MM, el‐Shanti H, Gitschier J. Homozygosity mapping places the acrodermatitis enteropathica gene on chromosomal region 8q24.3. Am J Hum Genet 68: 1055‐1060, 2001.
 189.Wang K, Zhou B, Kuo YM, Zemansky J, Gitschier J. A novel member of a zinc transporter family is defective in acrodermatitis enteropathica. Am J Hum Genet 71: 66‐73, 2002.
 190.Wang X, Wu Y, Zhou B. Dietary zinc absorption is mediated by ZnT1 in Drosophila melanogaster. FASEB J 23: 2650‐2661, 2009.
 191.Weaver BP, Andrews GK. Regulation of zinc‐responsive Slc39a5 (Zip5) translation is mediated by conserved elements in the 3'‐untranslated region. Biometals 25: 319‐335, 2012.
 192.Weaver BP, Dufner‐Beattie J, Kambe T, Andrews GK. Novel zinc‐responsive post‐transcriptional mechanisms reciprocally regulate expression of the mouse Slc39a4 and Slc39a5 zinc transporters (Zip4 and Zip5). Biol Chem 388: 1301‐1312, 2007.
 193.Wei Y, Fu D. Binding and transport of metal ions at the dimer interface of the Escherichia coli metal transporter YiiP. J Biol Chem 281: 23492‐23502, 2006.
 194.Wessels I, Cousins RJ. Zinc dyshomeostasis during polymicrobial sepsis in mice involves zinc transporter Zip14 and can be overcome by zinc supplementation. Am J Physiol Gastrointest Liver Physiol 309: G768‐G778, 2015.
 195.West AK, Stallings R, Hildebrand CE, Chiu R, Karin M, Richards RI. Human metallothionein genes: Structure of the functional locus at 16q13. Genomics 8: 513‐518, 1990.
 196.Whitehead MW, Thompson RP, Powell JJ. Regulation of metal absorption in the gastrointestinal tract. Gut 39: 625‐628, 1996.
 197.Whittaker P. Iron and zinc interactions in humans. Am J Clin Nutr 68: 442S‐446S, 1998.
 198.Wood RJ. Assessment of marginal zinc status in humans. J Nutr 130: 1350S‐1354S, 2000.
 199.Yasuno T, Okamoto H, Nagai M, Kimura S, Yamamoto T, Nagano K, Furubayashi T, Yoshikawa Y, Yasui H, Katsumi H, Sakane T, Yamamoto A. The disposition and intestinal absorption of zinc in rats. Eur J Pharm Sci 44: 410‐415, 2011.
 200.Yu Y, Wu A, Zhang Z, Yan G, Zhang F, Zhang L, Shen X, Hu R, Zhang Y, Zhang K, Wang F. Characterization of the GufA subfamily member SLC39A11/Zip11 as a zinc transporter. J Nutr Biochem 24: 1697‐1708, 2013.
 201.Yu YY, Kirschke CP, Huang L. Immunohistochemical analysis of ZnT1, 4, 5, 6, and 7 in the mouse gastrointestinal tract. J Histochem Cytochem 55: 223‐234, 2007.
 202.Zhao H, Butler E, Rodgers J, Spizzo T, Duesterhoeft S, Eide D. Regulation of zinc homeostasis in yeast by binding of the ZAP1 transcriptional activator to zinc‐responsive promoter elements. J Biol Chem 273: 28713‐28720, 1998.
 203.Zhao H, Eide D. The yeast ZRT1 gene encodes the zinc transporter protein of a high‐affinity uptake system induced by zinc limitation. Proc Natl Acad Sci U S A 93: 2454‐2458, 1996.
 204.Zhao H, Eide D. The ZRT2 gene encodes the low affinity zinc transporter in Saccharomyces cerevisiae. J Biol Chem 271: 23203‐23210, 1996.
 205.Zhao Y, Feresin RG, Falcon‐Perez JM, Salazar G. Differential Targeting of SLC30A10/ZnT10 Heterodimers to Endolysosomal Compartments Modulates EGF‐Induced MEK/ERK1/2 Activity. Traffic 17: 267‐288, 2016.
 206.Zheng D, Feeney GP, Kille P, Hogstrand C. Regulation of ZIP and ZnT zinc transporters in zebrafish gill: Zinc repression of ZIP10 transcription by an intronic MRE cluster. Physiol Genomics 34: 205‐214, 2008.
 207.Zyba SJ, Shenvi SV, Killilea DW, Holland TC, Kim E, Moy A, Sutherland B, Gildengorin V, Shigenaga MK, King JC. A moderate increase in dietary zinc reduces DNA strand breaks in leukocytes and alters plasma proteins without changing plasma zinc concentrations. Am J Clin Nutr 105: 343‐351, 2017.

 

Teaching Material

S. R. Hennigar, J. P. McClung. Zinc Transport in the Mammalian Intestine. Compr Physiol 9: 2019, 59-74.

Didactic Synopsis

Major Teaching Points:

  • Enterocytes, or absorptive epithelial cells of the small intestine, homeostatically regulate zinc absorption.
  • Enterocytes regulate zinc absorption by controlling the expression and localization of zinc transporters through transcriptional and post-transcriptional mechanisms.
  • Two families and 24 different zinc transporters have been identified, the zrt-irt-like protein family of zinc importers (ZIP1-14) and the zinc transporter family of zinc exporters (ZnT1-10).
  • Expression and localization of the various zinc transporters is tissue and cell specific.
  • The potential for zinc to be absorbed into circulation depends on the zinc status of the individual as well as the amount and bioavailability of zinc consumed.
  • Fractional zinc absorption increases in response to low zinc intakes and declines with increasing concentrations of ingested zinc.
  • Failure to regulate zinc transport in the small intestine may result in deficiency.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1 Teaching points: This figure depicts the relationship between zinc intake and zinc absorption. The amount of zinc absorbed depends on its bioavailability and zinc absorption plateaus with increased zinc intakes. Zinc in aqueous solutions is more bioavailable and readily absorbed than dietary zinc. Diets with high phytate:zinc molar ratios (15-23) are more readily absorbed than diets with low phytate:zinc molar ratios (5-7). Figure adapted, with permission, from (78, 181).

Figure 2 Teaching points: This figure shows the structure and function of the two families of zinc transporters. The arrows indicate the direction of zinc transport. (A) Zrt- irt-like proteins (ZIPs). Fourteen ZIPs have been identified and are encoded by the SLC39A1-14 genes. ZIPs are eight transmembrane proteins and function to import zinc into the cytosol, either from outside the cell or from an intracellular compartment. (B) Zinc transporters (ZnTs). Ten ZnTs have been identified and are encoded by the SLC30A1-10 genes. The majority of ZnTs are six transmembrane proteins and function to export zinc from the cytosol, either out of the cell or into an intracellular compartment. Both families homo- or heterodimerize to transport zinc.

Figure 3 Teaching points: This figure is a phylogenetic tree of the evolutionary relationships among (A) zrt- irt-like protein (ZIP) and (B) zinc transporter (ZnT) families. Subfamily classifications, which are based on transporter similarities, are shown in parentheses.

Figure 4 Teaching points: This figure illustrates the morphology of the mammalian small intestine and zinc transport in the enterocyte. The lining of the intestinal epithelium is composed of columnar absorptive enterocytes, mucous secreting goblet cells, and crypts of Lieberkühn. Enterocytes (inset) are a polarized cell type with distinct apical, lateral, and basolateral surfaces. The apical surface faces the intestinal lumen and is specialized for absorption with finger-like, microvilli projections that increase its surface area. The lateral and basolateral membranes contact adjacent cells and the basement membrane, respectively, and mediate the transport of nutrients into circulation. The inset shows zinc transport in the enterocyte in (A) zinc deficient and (B) zinc adequate or excess conditions. Zinc transporters whose intestinal localization have been reported are depicted. In response to low zinc conditions, ZIP4 translocates to the apical membrane and is primarily responsible for zinc uptake into the cell. In zinc adequate or excess conditions, paracellular zinc transport may override saturable zinc transport mechanisms. ZIP4 at the apical surface is rapidly endocytosed and degraded. Expression of intracellular metallothioneins and ZnT1 at the basolateral membrane increase to buffer the rise in labile zinc and export zinc from the cell, respectively. In contrast to low zinc conditions where ZIP5 is endocytosed and degraded, ZIP5 is localized to the basolateral surface in zinc adequate or excess conditions. ZnT2 and ZnT4 increase in response to zinc and transport zinc into secretory vesicles. ZnT5, ZnT6, and ZnT7 function to import zinc into the early secretory system and ZIP14 is found on the basolateral membrane; these transporters are generally refractory to the zinc status of the cell. ZnT5B is localized to the apical membrane and is capable of transporting zinc bidirectionally. EE, early endosome; LYS, lysosome; MT, metallothionein; SV, secretory vesicle.

 


Related Articles:

Iron Absorption
Principles of Membrane Transport
Iron Homeostasis in the Liver
Functional Morphology of Epithelium of the Small Intestine
Epithelial Transport
Epithelial Organization: The Gut and Beyond

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Zinc Transport in the Mammalian Intestine
 

How to Cite

Stephen R. Hennigar, James P. McClung. Zinc Transport in the Mammalian Intestine. Compr Physiol 2018, 9: 59-74. doi: 10.1002/cphy.c180001