Krüppel-like factor 4 regulates adaptive expression of the zinc transporter<i>Zip4</i>in mouse small intestine

Liuzzi, Juan P.; Guo, Liang; Chang, Soo-Eun; Cousins, Robert J.

doi:10.1152/ajpgi.90568.2008

Cited by 61 publications

(53 citation statements)

References 38 publications

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“…It was reported that zinc status had little effect on transcription of Zip4 but rather regulated mRNA stability both in cultured Hepa cells and mouse intestine (21). In contrast, a recent study found that Krüppel-like factor 4 bound to Zip4 promoter and its knockdown impaired Zip4 induction by zinc depletion in a mouse intestinal epithelial cell line (23). At the protein level, apart from endocytosis stimulated by low micromolar zinc (24), ubiquitination and degradation of ZIP4 were observed under higher zinc levels (25).…”

Section: Zinc Uptake Across the Apical Membrane Into Enterocytesmentioning

confidence: 94%

Dietary zinc absorption: A play of Zips and ZnTs in the gut

2010

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SummaryStudies on dietary zinc absorption are of fundamental nutritional significance, owing to the ubiquity of zinc in biological processes and the severe outcomes of zinc deficiency in humans. Insights into the molecular basis of dietary zinc absorption have advanced in recent years through functional characterization of zinc transporters in cell culture, immunohistochemical studies on rodent intestine and analysis of gene knockout mice. Zinc transporters with manifested expression in enterocytes include ZnT1, ZnT2, ZnT4, ZnT5, ZnT6, ZnT7, Zip4, and Zip5. Among them, ZIP4, the gene responsible for Acrodermatitis enteropathica, an inherited human zinc deficiency, mediates dietary zinc uptake into enterocytes across the apical membrane, while ZnT1 is involved in zinc efflux from enterocytes across the basolateral membrane into circulation. The intracellular trafficking pathways for zinc retention and movement between apical and basolateral sides of the enterocytes have yet to be defined. The utilization of Drosophila model in elucidating molecular mechanisms of dietary zinc absorption is also discussed in this review.

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Section: Zinc Uptake Across the Apical Membrane Into Enterocytesmentioning

confidence: 94%

Dietary zinc absorption: A play of Zips and ZnTs in the gut

2010

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“…Luminescence from firefly luciferase were normalized to renilla after 24 h incubation with 100 μM ZnSO 4 . These methods have been described in detail earlier (42,43). See SI Methods.…”

Section: Methodsmentioning

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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“…Up-regulation of SLC39A4 transcripts during zinc deficiency might be due to mRNA stabilization rather than increased transcription of its gene (Weaver et al, 2007). However, the Krüppel-like factor 4 (KLF4) transcription factor was suggested to be responsible for regulating ZIP4 expression (Liuzzi et al, 2009). KLF4 is abundant in the intestine, induced during zinc restriction in mice, and binds to the mouse Slc39a4 promoter (Liuzzi et al, 2009).…”

Section: Zinc Uptake and Its Regulationmentioning

confidence: 99%

The SLC39 family of zinc transporters

Jeong

Eide

2013

Molecular Aspects of Medicine

389

330

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Zinc is a trace element nutrient that is essential for life. This mineral serves as a cofactor for enzymes that are involved in critical biochemical processes and it plays many structural roles as well. At the cellular level, zinc is tightly regulated and disruption of zinc homeostasis results in serious physiological or pathological issues. Despite the high demand for zinc in cells, free or labile zinc must be kept at very low levels. In humans, two major zinc transporter families, the SLC30 (ZnT) family and SLC39 (ZIP) family control cellular zinc homeostasis. This review will focus on the SLC39 transporters. SLC39 transporters primarily serve to pass zinc into the cytoplasm, and play critical roles in maintaining cellular zinc homeostasis. These proteins are also significant at the organismal level, and studies are revealing their link to human diseases. Therefore, we will discuss the function, structure, physiology, and pathology of SLC39 transporters.

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Krüppel-like factor 4 regulates adaptive expression of the zinc transporterZip4in mouse small intestine

Abstract: Liuzzi JP, Guo L, Chang S-M, Cousins RJ. Krüppel-like factor 4 regulates adaptive expression of the zinc transporter Zip4 in mouse small intestine.

Cited by 61 publications

References 38 publications

Dietary zinc absorption: A play of Zips and ZnTs in the gut

Dietary zinc absorption: A play of Zips and ZnTs in the gut

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

The SLC39 family of zinc transporters

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