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      Psychological stress induced zinc accumulation and up-regulation of ZIP14 and metallothionein in rat liver

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          Abstract

          Background

          Zinc is necessary for normal liver function; and vice versa, the liver plays a central role in zinc homeostasis. The aim of present study is to assess the effects of repeated psychological stress (PS) on the zinc metabolism and related mechanism involved in zinc homeostasis in rat liver.

          Methods

          In present study, we used communication box to create PS model and investigated the serum corticosterone (CORT), zinc level in serum and liver, liver metallothionein (MT) content and ZRT/IRT-like Protein 14 (ZIP14) mRNA expression.

          Results

          The results showed that the serum CORT level increased and serum zinc level decreased significantly after 7 d and 14 d PS treatment. Meanwhile, zinc and MT contents in liver were elevated after 14 d PS exposure, while those in 7 d PS exposure group did not change. ZIP14 mRNA was expressed markedly at 7 d after the onset of PS, while Zip14 mRNA expression in the liver after 14 d PS exposure reached normal level compared with control group.

          Conclusions

          The results suggest that PS exposure could induce hypozincemia, which might be related to liver zinc accumulation because of high level of MT through glucocorticoid-mediated MT synthesis and ZIP14 expression induced by interleukin-6.

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          Zinc biochemistry: from a single zinc enzyme to a key element of life.

          Wolfgang Maret (2012)
          The nutritional essentiality of zinc for the growth of living organisms had been recognized long before zinc biochemistry began with the discovery of zinc in carbonic anhydrase in 1939. Painstaking analytical work then demonstrated the presence of zinc as a catalytic and structural cofactor in a few hundred enzymes. In the 1980s, the field again gained momentum with the new principle of "zinc finger" proteins, in which zinc has structural functions in domains that interact with other biomolecules. Advances in structural biology and a rapid increase in the availability of gene/protein databases now made it possible to predict zinc-binding sites from metal-binding motifs detected in sequences. This procedure resulted in the definition of zinc proteomes and the remarkable estimate that the human genome encodes ∼3000 zinc proteins. More recent developments focus on the regulatory functions of zinc(II) ions in intra- and intercellular information transfer and have tantalizing implications for yet additional functions of zinc in signal transduction and cellular control. At least three dozen proteins homeostatically control the vesicular storage and subcellular distribution of zinc and the concentrations of zinc(II) ions. Novel principles emerge from quantitative investigations on how strongly zinc interacts with proteins and how it is buffered to control the remarkably low cellular and subcellular concentrations of free zinc(II) ions. It is fair to conclude that the impact of zinc for health and disease will be at least as far-reaching as that of iron.
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            Interleukin-6 regulates the zinc transporter Zip14 in liver and contributes to the hypozincemia of the acute-phase response.

            Tolunay Aydemir, Mitchell Knutson, Tomas Ganz … (2005)
            Infection and inflammation produce systemic responses that include hypozincemia and hypoferremia. The latter involves regulation of the iron transporter ferroportin 1 by hepcidin. The mechanism of reduced plasma zinc is not known. Transcripts of the two zinc transporter gene families (ZnT and Zip) were screened for regulation in mouse liver after turpentine-induced inflammation and LPS administration. Zip14 mRNA was the transporter transcript most up-regulated by inflammation and LPS. IL-6 knockout (IL-6(-/-)) mice did not exhibit either hypozincemia or the induction of Zip14 with turpentine inflammation. However, in IL-6(-/-) mice, LPS produced a milder hypozincemic response but no Zip14 induction. Northern analysis showed Zip14 up-regulation was specific for the liver, with one major transcript. Immunohistochemistry, using an antibody to an extracellular Zip14 epitope, showed both LPS and turpentine increased abundance of Zip14 at the plasma membrane of hepatocytes. IL-6 produced increased expression of Zip14 in primary hepatocytes cultures and localization of the protein to the plasma membrane. Transfection of mZip14 cDNA into human embryonic kidney cells increased zinc uptake as measured by both a fluorescent probe for free Zn(2+) and (65)Zn accumulation, as well as by metallothionein mRNA induction, all indicating that Zip14 functions as a zinc importer. Zip14 was localized in plasma membrane of the transfected cells. These in vivo and in vitro experiments demonstrate that Zip14 expression is up-regulated through IL-6, and that this zinc transporter most likely plays a major role in the mechanism responsible for hypozincemia that accompanies the acute-phase response to inflammation and infection.
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              Zinc and the modulation of redox homeostasis.

              Patricia I. Oteiza (2012)
              Zinc, a redox-inactive metal, has been long viewed as a component of the antioxidant network, and growing evidence points to its involvement in redox-regulated signaling. These actions are exerted through several mechanisms based on the unique chemical and functional properties of zinc. Overall, zinc contributes to maintaining the cell redox balance through various mechanisms including: (i) the regulation of oxidant production and metal-induced oxidative damage; (ii) the dynamic association of zinc with sulfur in protein cysteine clusters, from which the metal can be released by nitric oxide, peroxides, oxidized glutathione, and other thiol oxidant species; (iii) zinc-mediated induction of the zinc-binding protein metallothionein, which releases the metal under oxidative conditions and acts per se as a scavenging oxidant; (iv) the involvement of zinc in the regulation of glutathione metabolism and of the overall protein thiol redox status; and (v) a direct or indirect regulation of redox signaling. Findings of oxidative stress, altered redox signaling, and associated cell/tissue dysfunction in cell and animal models of zinc deficiency highlight the relevant role of zinc in the preservation of cell redox homeostasis. However, although the participation of zinc in antioxidant protection, redox sensing, and redox-regulated signaling is accepted, the molecules, targets, and mechanisms involved are still partially known and the subject of active research. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Journal ID (nlm-ta): BMC Gastroenterol
                Journal ID (iso-abbrev): BMC Gastroenterol
                Title: BMC Gastroenterology
                Publisher: BioMed Central
                ISSN (Electronic): 1471-230X
                Publication date Collection: 2014
                Publication date (Electronic): 18 February 2014
                Volume: 14
                Page: 32
                Affiliations
                [1 ]Department of Naval Hygiene, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, PR China
                [2 ]Department of Immunology, Second Military Medical University, No. 800 Xiangyin Road, Shanghai 200433, China
                [3 ]Department of Medical Oncology, Changzheng Hospital, No. 64 Hetian Road, Shanghai 200070, China
                Article
                Publisher ID: 1471-230X-14-32
                DOI: 10.1186/1471-230X-14-32
                PMC ID: 3931483
                PubMed ID: 24548602
                SO-VID: 63d8e8dd-66ea-4fac-8e9c-2007245fd36d
                Copyright © Copyright © 2014 Tian et al.; licensee BioMed Central Ltd.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.

                History
                Date received : 3 May 2013
                Date accepted : 13 February 2014
                Categories
                Subject: Research Article

                ScienceOpen disciplines: Gastroenterology & Hepatology
                Keywords: psychological stress,zip14,zinc,liver,corticosterone,metallothionein
                Data availability:
                ScienceOpen disciplines: Gastroenterology & Hepatology
                Keywords: psychological stress, zip14, zinc, liver, corticosterone, metallothionein

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