Introduction. Zinc deficiency affects more than one billion children under 5 years old and is responsible for 400,000 deaths annually worldwide. Secretion from the exocrine pancreas is a major route of endogenous zinc loss. Thus it plays an important role in the maintenance of zinc homeostasis. The molecular mechanisms, pathways, and the transporters for pancreatic zinc secretion are still not clear. Glucocorticoid therapy increases zinc excretion, and causes a rapid depression of serum zinc. So far, no zinc transporter has been found to be regulated by glucocorticoid hormones.

Objectives. The major aims were to identify the zinc transporters in exocrine pancreas and evaluate their role in zinc secretion and to define physiological effects of zinc transporter expression in pancreatic acinar cells.

Results. Two highly expressed zinc transporters, ZnT1 and ZnT2 were identified in acinar cells, the major cell type in the exocrine pancreas. Immunofluorescence localized ZnT1 and ZnT2 to the plasma membrane and zymogen granules, respectively. Dietary zinc restriction significantly decreased the zinc concentration over 50% in both pancreatic cell cytoplasm and in zymogen granules and was correlated with decreased expression of ZnT1 and ZnT2. In contrast, with an up-regulated ZnT1 and ZnT2 observed after oral zinc administration produced an increase in pancreatic zinc content. Zinc stimulated ZnT1 expression in a dose-dependent manner in rat pancreatic AR42J cells. ZnT2 was stimulated by 100 nM dexamethasone during AR42J differentiation. In agreement, 10 mg/kg body weight dexamethasone administered to mice induced ZnT2 expression and resulted in a reduction in pancreatic zinc content. ZnT2 siRNA in AR42J cells caused an increase in cytoplasmic zinc and decreased zymogen granule zinc, which further shows that ZnT2 mediates the sequestration of zinc into zymogen granules. A crucial metal response element was found in the ZnT2 promoter that confers the responsiveness to zinc. Both glucocorticoid receptor and Stat5 signaling were required in dexamethasone induced ZnT2 expression.

Conclusions. ZnT1 controls zinc efflux directly across the apical membrane in a zinc-dependent manner, whereas ZnT2 participates in zinc sequestration into secretory granules. The two transporters appear to function closely in acinar cell zinc secretion and constitute an important component of the entero-pancreatic zinc circulation.

Significance. Understanding of the molecular mechanisms and regulation of endogenous zinc loss via pancreatic secretion is an important part of zinc homeostasis. The results of this study suggest that normal pancreatic acinar cell function is an essential physiologic component that influences body zinc retention and prevents zinc deficiency.