FIG. 2.

Overview of zinc homeostasis. Twenty four different genes encode proteins that may be involved in the uptake (Zip genes) or efflux (ZnT genes) of this metal in a cell-specific, developmentally regulated, and zinc-regulated manner. The functions of many of these genes remain to be determined. Therefore, this cartoon provides only a superficial and static view of zinc homeostasis. ZIP4 plays a critical role in the absorption of dietary zinc by ENTEROCYTE/ENDODERM cells when zinc is limiting, but other transporters must also play important roles. Zinc is thought to be exported into portal blood or into the conceptus by ZnT1 localized on the basolateral membrane. Other ZnT proteins (i.e. ZnT4) also likely play a role in this process. ZIP5 is localized to the basolateral membranes of enterocytes, endoderm cells and pancreatic acinar cells where it may serve to remove zinc from the blood when zinc is replete. In peripheral tissues (GENERIC CELL), zinc is probably taken up by various ZIP transporters localized on the plasma membrane. To date ZIPs1, 2, 3, 6, 8, 10, and 14 have each been shown to have zinc transport activity in transfection or oocyte injection studies, and most show tissue-specific patterns of expression. Inside the cell, free zinc levels are kept low and zinc can be bound to MT or transported into secretory vesicles, endosomes/lysosomes or zincosomes by ZnT2 and ZnT4. Zinc activates the zinc-sensing transcription factor MTF-1 which regulates transcription of the mouse Mt-I/II and Znt1 genes and represses expression of Zip10 in an effort to control excess zinc. ZnTs2–7 participate in the delivery of zinc into the secretory pathway, whereas ZIP7 may transport zinc out of the Golgi apparatus into the cytoplasm. ZnT3 transports zinc into glutamate containing vesicles in the brain whereas ZnT8 transports zinc into pancreatic β-cell insulin secretory granules. ZIP4 is expressed in β-cells, but its localization in those cells has not been reported.