Zinc Homeostasis in Humans

King, Janet C.; Shames, David M.; Woodhouse, Leslie R.

doi:10.1093/jn/130.5.1360s

Cited by 479 publications

(325 citation statements)

References 25 publications

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“…In mammals fed a diet with adequate zinc, this metal is absorbed by intestinal enterocytes, but excess zinc is released through the pancreas and back through the small intestine (King et al, 2000;Hambidge and Krebs, 2001). Under zinc-deficient conditions, zinc absorption by the small intestine increases, and zinc release from the pancreas and small intestine decreases (Hambidge and Krebs, 2001).…”

Section: Introductionmentioning

confidence: 99%

Novel zinc-responsive post-transcriptional mechanisms reciprocally regulate expression of the mouse Slc39a4 and Slc39a5 zinc transporters (Zip4 and Zip5)

Weaver

Dufner-Beattie

Kambe

et al. 2007

BCHM

141

163

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Dietary zinc deficiency in mice is accompanied by enhanced expression of the zinc uptake transporter Slc39a4 (Zip4) and repressed expression of Slc39a5 (Zip5) in tissues which regulate zinc homeostasis (intestine, pancreas and visceral yolk sac). Herein, mechanisms controlling this differential expression were investigated. The induction of Zip4 mRNA during zinc deficiency, and its repression in response to zinc repletion were found to reflect changes in Zip4 mRNA stability and not changes in the relative rate of transcription of this gene. During zinc deficiency, ZIP4 protein levels are increased and this protein is localized on the apical membranes. Administration of an oral gavage of zinc caused ZIP4 internalization and degradation in enterocytes and visceral endoderm cells. Similarly, ZIP4 is induced by zinc deficiency in cultured mouse Hepa cells and is rapidly degraded in response to added zinc. Zip5 mRNA abundance does not change in response to zinc, but the translation of this mRNA was found to be zinc-responsive. During zinc deficiency, Zip5 mRNA remains associated with polysomes, while the protein is internalized and degraded in enterocytes, acinar cells and endoderm cells. After zinc-gavage, ZIP5 is rapidly resynthesized and targeted to the basolateral membranes of these cell types.

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Section: Introductionmentioning

confidence: 99%

Novel zinc-responsive post-transcriptional mechanisms reciprocally regulate expression of the mouse Slc39a4 and Slc39a5 zinc transporters (Zip4 and Zip5)

Weaver

Dufner-Beattie

Kambe

et al. 2007

BCHM

141

163

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“…We hypothesize that inadequate nutrition is a significant environmental risk and bears a significant impact on the susceptibility to cancer. A significant portion of the North American population does not get adequate zinc (6). Ten percent of the U.S. population consumes less than half the recommended daily allowance for zinc, especially those who consume little meat and͞or consume high phytate-containing food sources (7).…”

mentioning

confidence: 99%

Low intracellular zinc induces oxidative DNA damage, disrupts p53, NFκB, and AP1 DNA binding, and affects DNA repair in a rat glioma cell line

Ames

2002

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

359

266

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Approximately 10% of the U.S. population ingests <50% of the current recommended daily allowance for zinc. We investigate the effect of zinc deficiency on DNA damage, expression of DNA-repair enzymes, and downstream signaling events in a cell-culture model. Low zinc inhibited cell growth of rat glioma C6 cells and increased oxidative stress. Low intracellular zinc increased DNA single-strand breaks (comet assay). Zinc-deficient C6 cells also exhibited an increase in the expression of the zinc-containing DNA-repair proteins p53 and apurinic endonuclease (APE). Repletion with zinc restored cell growth and reversed DNA damage. APE is a multifunctional protein that not only repairs DNA but also controls DNA-binding activity of many transcription factors that may be involved in cancer progression. The ability of the transcription factors p53, nuclear factor B, and activator protein 1 (AP1) to bind to consensus DNA sequences was decreased markedly with zinc deficiency, as assayed by electrophoretic mobility-shift assays. Thus, low intracellular zinc status causes oxidative DNA damage and induces DNA-repair protein expression, but binding of p53 and important downstream signals leading to proper DNA repair are lost without zinc.

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“…At the organismal level, tissue-specific homeostatic roles are superimposed on these cellular mechanisms. Zinc homeostasis in mammals is primarily regulated through the control of zinc absorption in the intestine and the loss of endogenous zinc in the intestine and through both pancreatic and liver excretion (1)(2)(3). Under conditions of extreme zinc overload or deficiency, excretion of zinc through the kidney into urine is also a contributing factor to homeostasis.…”

mentioning

confidence: 99%

The Mammalian Zip5 Protein Is a Zinc Transporter That Localizes to the Basolateral Surface of Polarized Cells

Wang

Kim

Petris

et al. 2004

Journal of Biological Chemistry

138

102

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The mouse and human Zip5 proteins are members of the ZIP family of metal ion transporters. In this study, we present evidence that mouse Zip5 is a zinc uptake transporter that is specific for Zn(II) over other potential metal ion substrates. We also show that, unlike many other mammalian ZIP proteins, the endocytic removal of mZip5 from the plasma membrane is not triggered by zinc treatment. Thus, the activity of mZip5 does not appear to be down-regulated by zinc repletion. Zip5 expression is restricted to many tissues important for zinc homeostasis, including the intestine, pancreas, liver, and kidney. Zip5 is similar in sequence to the Zip4 protein, which is involved in the uptake of dietary zinc. Co-expression of Zip4 and Zip5 in the intestine led to the hypothesis that these proteins play overlapping roles in the uptake of dietary zinc across the apical membrane of intestinal enterocytes. Surprisingly, however, we found that mZip5 localizes specifically to the basolateral membrane of polarized Madin-Darby canine kidney cells. These observations suggest that Zip5 plays a novel role in polarized cells by carrying out serosal-to-mucosal zinc transport. Furthermore, given its expression in tissues important to zinc homeostasis, we propose that Zip5 plays a central role in controlling organismal zinc status.

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Zinc Homeostasis in Humans

Cited by 479 publications

References 25 publications

Novel zinc-responsive post-transcriptional mechanisms reciprocally regulate expression of the mouse Slc39a4 and Slc39a5 zinc transporters (Zip4 and Zip5)

Novel zinc-responsive post-transcriptional mechanisms reciprocally regulate expression of the mouse Slc39a4 and Slc39a5 zinc transporters (Zip4 and Zip5)

Low intracellular zinc induces oxidative DNA damage, disrupts p53, NFκB, and AP1 DNA binding, and affects DNA repair in a rat glioma cell line

The Mammalian Zip5 Protein Is a Zinc Transporter That Localizes to the Basolateral Surface of Polarized Cells

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