Differential Regulation of Zinc Transporter 1, 2, and 4 mRNA Expression by Dietary Zinc in Rats

Liuzzi, Juan P.; Blanchard, Raymond K.; Cousins, Robert J.

doi:10.1093/jn/131.1.46

Cited by 215 publications

(181 citation statements)

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“…In addition, the expression levels of ZnT1 mRNA in the small intestine are not affected by low zinc diet. 39,40) Since no regional difference in the mRNA level of ZnT1 was observed between three segments of the rat intestine in this study, ZnT1 might be expressed highly enough for the transport of zinc, which is absorbed by ZIP4, back into blood stream. Consequently, V max and K d determined with the in vitro permeation study may be not parameters of a single transporter but hybrid parameters of two or more transporters.…”

Section: )mentioning

confidence: 70%

<i>In Vitro</i> Study on the Transport of Zinc across Intestinal Epithelial Cells Using Caco-2 Monolayers and Isolated Rat Intestinal Membranes

Yasuno

Okamoto

Nagai

et al. 2012

Biological & Pharmaceutical Bulletin

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The variety of physiologic and biologic functions of zinc is fascinating and could be applicable to medicine. Our previous studies demonstrated that the absorption of zinc after oral administration to rats is dose-dependent. In order to clarify the detailed mechanism of the dose-dependent in vivo absorption, the transport of zinc across intestinal epithelial cells was investigated using Caco-2 monolayers and isolated rat intestinal membranes. The permeation of zinc across Caco-2 monolayers is concentration-dependent, and both saturable and nonsaturable components are involved. The Michaelis constant and maximum transport rate for saturable transport are 11.7 μM and 31.8 pmol min 1 cm 2 , respectively; the permeability coefficient for nonsaturable trasnport is 2.37 10 6 cm s 1 . These parameters for permeation across membranes isolated from duodenum, ileum, and jejunum of rats are similar with those of Caco-2 cells. The comparison of the parameters for permeation across isolated intestinal membrane suggests that the major site of intestinal zinc absorption in rats is the duodenum. The maximum rate of zinc transport across the isolated intestinal membrane (V max ) shows no correlation with mRNA expression of ZIP4, ZIP5 or ZnT1 in rats, but shows an inverse correlation with that of metallothioneins (MTs). This finding may be partly explained by the buffering role of metallothionein in intestinal absorption. The saturable transport of zinc is not simply determined only by the influx transporter, ZIP4, since three influx and efflux transporters are involved in the transport of zinc.

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Section: )mentioning

confidence: 70%

<i>In Vitro</i> Study on the Transport of Zinc across Intestinal Epithelial Cells Using Caco-2 Monolayers and Isolated Rat Intestinal Membranes

Yasuno

Okamoto

Nagai

et al. 2012

Biological & Pharmaceutical Bulletin

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“…The expression of ZnT2 has been found to be regulated by zinc in certain tissues, e.g. pancreas, small intestine, prostate, and bloodbrain barrier (10,(29)(30)(31). As shown in the current experiments, zinc regulation is conferred by the consensus MRE located at þ53 to þ59 of the murine ZnT2 gene, which when mutated The pancreatic acinar AR42J cell model has been widely used to characterize effects of glucocorticoid hormones on secretory activity of the exocrine pancreas and regulation of the amylase gene (16,32,33).…”

Section: Discussionmentioning

confidence: 99%

STAT5-glucocorticoid receptor interaction and MTF-1 regulate the expression of ZnT2 (Slc30a2) in pancreatic acinar cells

Guo

Lichten

Ryu

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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112

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The exocrine pancreas plays an important role in endogenous zinc loss by regulating excretion into the intestinal tract and hence influences the dietary zinc requirement. The present experiments show that the zinc transporter ZnT2 (Slc30a2) is localized to the zymogen granules and that dietary zinc restriction in mice decreased the zinc concentration of zymogen granules and ZnT2 expression. Excess zinc given orally increased ZnT2 expression and was associated with increased pancreatic zinc accumulation. Rat AR42J acinar cells when induced into a secretory phenotype, using the glucocorticoid analog dexamethasone (DEX), exhibited increased ZnT2 expression and labile zinc as measured with a fluorophore. DEX administrated to mice also induced ZnT2 expression that accompanied a reduction of the pancreatic zinc content. ZnT2 promoter analyses identified elements required for responsiveness to zinc and DEX. Zinc regulation was traced to a MRE located downstream from the ZnT2 transcription start site. Responsiveness to DEX is produced by two upstream STAT5 binding sites that require the glucocorticoid receptor for activation. ZnT2 knockdown in the AR42J cells using siRNA resulted in increased cytoplasmic zinc and decreased zymogen granule zinc that further demonstrated that ZnT2 may mediate the sequestration of zinc into zymogen granules. We conclude, based upon experiments with intact mice and pancreatic acinar cells in culture, that ZnT2 participates in zinc transport into pancreatic zymogen granules through a glucocorticoid pathway requiring glucocorticoid receptor and STAT5, and zinc-regulated signaling pathways requiring MTF-1. The ZnT2 transporter appears to function in a physiologically responsive manner involving entero-pancreatic zinc trafficking.M ammalian zinc homeostasis is maintained through a balance between gastrointestinal absorption, tissue turnover, and biliary, pancreatic, and intestinal secretions into the intestinal lumen (1). Under conditions of normal dietary zinc intake, substantial amounts of zinc are released into the small intestine from the exocrine pancreas (2, 3). These secretions represent a major component of calculations used to establish the dietary zinc requirement for humans.Over 85% of the pancreas is comprised of exocrine cells (4). Localization studies have shown that pancreatic zinc is concentrated in the granules of acinar cells, where digestive proenzymes are also stored prior to exocytosis through the apical membrane for entry into the intestinal lumen. Abnormal zinc metabolism has been reported after pancreatectomy (5-7). Zinc deficiency causes pancreatic acinar cells to become depleted of zinc (8,9). Radiotracer studies have shown that the pancreas exhibits high rates of zinc turnover [reviewed in (10)]. The exocrine pancreas is a target organ of zinc toxicosis. Excessive dietary zinc alters acinar cell structure, and produces necrosis, causing depletion of zymogen granules and reduces digestive enzyme secretion (11-13). This sensitivity to zinc supports the need for tight re...

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“…Knockout mice lacking ZnT3 are viable but display a severe depletion of zinc in synaptic vesicles [21]. ZnT4 is expressed ubiquitously [22,23] and localized to cytoplasmic organelles [24,25], although its exact subcellular distribution remains unsettled. Mice of the lethal milk (lm) strain carry a nonsense mutation in Znt4 [22]; the milk of these mice is depleted of zinc and do not support the normal development of pups.…”

Section: Introductionmentioning

confidence: 99%

Zinc transporter 2 (SLC30A2) can suppress the vesicular zinc defect of adaptor protein 3-depleted fibroblasts by promoting zinc accumulation in lysosomes

Falcón‐Pérez

Dell’Angelica

2007

Experimental Cell Research

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Zinc accumulation in the lumen of cytoplasmic vesicles is one of the mechanisms by which cells can store significant amounts of this essential but potentially toxic biometal. Previous studies had demonstrated reduced vesicular zinc levels in fibroblasts from mutant mice deficient in adaptor protein 3 (AP-3), a complex involved in protein trafficking to late endosomes and lysosomes. We have observed a similar phenotype in the human fibroblastoid cell line, M1, upon small interference RNA-mediated AP-3 knockdown. A survey of the expression and localization of zinc transporter (ZnT) family members identified ZnT2, ZnT3 and ZnT4 as likely mediators of vesicular zinc accumulation in M1 cells. Expression of green fluorescence protein (GFP)-tagged ZnT2 and ZnT3 promoted accumulation of vesicular zinc as visualized using the indicator zinquin. Moreover, GFPZnT2 overexpression elicited a significant accumulation of zinc within mature lysosomes, which in untransfected M1 cells contained little or no chelatable zinc, and restored the zinc storage capability of AP-3-deficient cells. These results suggest that ZnT2 can facilitate vesicular zinc accumulation independently of AP-3 function, and validate the M1 fibroblastoid line as a human cell culture system amenable to the study of vesicular zinc regulation using techniques compatible with functional genomic approaches.

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Differential Regulation of Zinc Transporter 1, 2, and 4 mRNA Expression by Dietary Zinc in Rats

Cited by 215 publications

References 24 publications

<i>In Vitro</i> Study on the Transport of Zinc across Intestinal Epithelial Cells Using Caco-2 Monolayers and Isolated Rat Intestinal Membranes

<i>In Vitro</i> Study on the Transport of Zinc across Intestinal Epithelial Cells Using Caco-2 Monolayers and Isolated Rat Intestinal Membranes

STAT5-glucocorticoid receptor interaction and MTF-1 regulate the expression of ZnT2 (Slc30a2) in pancreatic acinar cells

Zinc transporter 2 (SLC30A2) can suppress the vesicular zinc defect of adaptor protein 3-depleted fibroblasts by promoting zinc accumulation in lysosomes

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