Research advances defining how zinc is transported into and out of cells and organelles have increased exponentially within the past five years. Research has progressed through application of molecular techniques including genomic analysis, cell transfection, RNA interference, kinetic analysis of ion transport, and application of cell and animal models including knockout mice. The knowledge base has increased for most of 10 members of the ZnT family and 14 members of the Zrt-, Irt-like protein (ZIP) family. Relative to the handling of dietary zinc is the involvement of ZnT1, ZIP4, and ZIP5 in intestinal zinc transport, involvement of ZIP10 and ZnT1 in renal zinc reabsorption, and the roles of ZIP5, ZnT2, and ZnT1 in pancreatic release of endogenous zinc. These events are major factors in regulation of zinc homeostasis. Other salient findings are the involvement of ZnT2 in lactation, ZIP14 in the hypozincemia of inflammation, ZIP6, ZIP7, and ZIP10 in metastatic breast cancer, and ZnT8 in insulin processing and as an autoantigen in diabetes.

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Infection and inflammation produce systemic responses that include hypozincemia and hypoferremia. The latter involves regulation of the iron transporter ferroportin 1 by hepcidin. The mechanism of reduced plasma zinc is not known. Transcripts of the two zinc transporter gene families (ZnT and Zip) were screened for regulation in mouse liver after turpentine-induced inflammation and LPS administration. Zip14 mRNA was the transporter transcript most up-regulated by inflammation and LPS. IL-6 knockout (IL-6 ؊/؊ ) mice did not exhibit either hypozincemia or the induction of Zip14 with turpentine inflammation. However, in IL-6 ؊/؊ mice, LPS produced a milder hypozincemic response but no Zip14 induction. Northern analysis showed Zip14 up-regulation was specific for the liver, with one major transcript. Immunohistochemistry, using an antibody to an extracellular Zip14 epitope, showed both LPS and turpentine increased abundance of Zip14 at the plasma membrane of hepatocytes. IL-6 produced increased expression of Zip14 in primary hepatocytes cultures and localization of the protein to the plasma membrane. Transfection of mZip14 cDNA into human embryonic kidney cells increased zinc uptake as measured by both a fluorescent probe for free Zn 2؉ and 65 Zn accumulation, as well as by metallothionein mRNA induction, all indicating that Zip14 functions as a zinc importer. Zip14 was localized in plasma membrane of the transfected cells. These in vivo and in vitro experiments demonstrate that Zip14 expression is up-regulated through IL-6, and that this zinc transporter most likely plays a major role in the mechanism responsible for hypozincemia that accompanies the acute-phase response to inflammation and infection.endotoxemia ͉ inflammation ͉ hepatic ͉ Slc39a14 ͉ knockout mice

▪ Abstract  New insights into mammalian zinc metabolism have been acquired through the identification and characterization of zinc transporters. These proteins all have transmembrane domains, and are encoded by two solute-linked carrier (SLC) gene families: ZnT (SLC30) and Zip (SLC39). There are at least 9 ZnT and 15 Zip transporters in human cells. They appear to have opposite roles in cellular zinc homeostasis. ZnT transporters reduce intracellular zinc availability by promoting zinc efflux from cells or into intracellular vesicles, while Zip transporters increase intracellular zinc availability by promoting extracellular zinc uptake and, perhaps, vesicular zinc release into the cytoplasm. Both the ZnT and Zip transporter families exhibit unique tissue-specific expression, differential responsiveness to dietary zinc deficiency and excess, and differential responsiveness to physiologic stimuli via hormones and cytokines.