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Zinc Transport in the Mammalian Intestine

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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.

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 ().
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 (). 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 ().


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 (). 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.
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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.

 


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