The Zinc Transporter, Slc39a7 (Zip7) Is Implicated in Glycaemic Control in Skeletal Muscle Cells

PLOS ONE, Dec 2019

Dysfunctional zinc signaling is implicated in disease processes including cardiovascular disease, Alzheimer's disease and diabetes. Of the twenty-four mammalian zinc transporters, ZIP7 has been identified as an important mediator of the ‘zinc wave’ and in cellular signaling. Utilizing siRNA targeting Zip7 mRNA we have identified that Zip7 regulates glucose metabolism in skeletal muscle cells. An siRNA targeting Zip7 mRNA down regulated Zip7 mRNA 4.6-fold (p = 0.0006) when compared to a scramble control. This was concomitant with a reduction in the expression of genes involved in glucose metabolism including Agl, Dlst, Galm, Gbe1, Idh3g, Pck2, Pgam2, Pgm2, Phkb, Pygm, Tpi1, Gusb and Glut4. Glut4 protein expression was also reduced and insulin-stimulated glycogen synthesis was decreased. This was associated with a reduction in the mRNA expression of Insr, Irs1 and Irs2, and the phosphorylation of Akt. These studies provide a novel role for Zip7 in glucose metabolism in skeletal muscle and highlight the importance of this transporter in contributing to glycaemic control in this tissue.

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The Zinc Transporter, Slc39a7 (Zip7) Is Implicated in Glycaemic Control in Skeletal Muscle Cells

Slc39a7 (Zip7) Is Implicated in Glycaemic Control in Skeletal Muscle Cells. PLoS ONE 8(11): e79316. doi:10.1371/journal.pone.0079316 The Zinc Transporter, Slc39a7 (Zip7 ) Is Implicated in Glycaemic Control in Skeletal Muscle Cells Stephen A. Myers 0 Alex Nield 0 Guat-Siew Chew 0 Mark A. Myers 0 Barbara Bardoni, CNRS UMR7275, France 0 1 Collaborative Research Network and the School of Health Sciences, University of Ballarat , Mount Helen Campus, Victoria , Australia , 2 School of Health Sciences, University of Ballarat , Mount Helen Campus, Victoria , Australia Dysfunctional zinc signaling is implicated in disease processes including cardiovascular disease, Alzheimer's disease and diabetes. Of the twenty-four mammalian zinc transporters, ZIP7 has been identified as an important mediator of the 'zinc wave' and in cellular signaling. Utilizing siRNA targeting Zip7 mRNA we have identified that Zip7 regulates glucose metabolism in skeletal muscle cells. An siRNA targeting Zip7 mRNA down regulated Zip7 mRNA 4.6-fold (p = 0.0006) when compared to a scramble control. This was concomitant with a reduction in the expression of genes involved in glucose metabolism including Agl, Dlst, Galm, Gbe1, Idh3g, Pck2, Pgam2, Pgm2, Phkb, Pygm, Tpi1, Gusb and Glut4. Glut4 protein expression was also reduced and insulin-stimulated glycogen synthesis was decreased. This was associated with a reduction in the mRNA expression of Insr, Irs1 and Irs2, and the phosphorylation of Akt. These studies provide a novel role for Zip7 in glucose metabolism in skeletal muscle and highlight the importance of this transporter in contributing to glycaemic control in this tissue. - Funding: This study was funded by a School of Health Sciences Seeding Grant, University of Ballarat, Victoria Australia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. . These authors contributed equally to this work. Cellular zinc storage, release and distribution are controlled by a family of zinc transporters and metallothioneins. In mammals two families of zinc transporters exist: the zinc efflux (Slc30/ZnT) and the zinc influx (Slc39/ZIP) proteins [1]. ZnT proteins transport zinc out of the cell or into subcellular compartments in the presence of high cytoplasmic zinc. In contrast, ZIP proteins transport zinc into the cell or out of subcellular compartments when cytosolic zinc is low or depleted [2]. There is increasing interest in the importance of zinc transporters in diseases associated with dysfunctional cellular signaling. In particular, a significant role for these transporters in maintaining essential glucose and lipid metabolism has been identified. For example, in myocytes isolated from the femoral muscle of ZnT7 knockout mice, a reduction in insulin signaling pathway activity was observed [3]. The ZnT7 null mice were susceptible to diet-induced glucose intolerance and insulin resistance and this was associated with a decrease in the expression of the insulin receptor, insulin receptor substrate 2 and Akt1 [3]. ZnT3, ZnT5 and ZnT8 gene expression are differentially regulated by glucose in INS-IE cells, and streptozotocin-treated ZnT3 null mice have decreased insulin gene expression and insulin secretion that resulted in hyperglycemia [4]. Moreover, ZnT8 plays a critical role in the synthesis and secretion of insulin and therefore represents a pharmacological target for treating disorders of insulin secretion including diabetes [5]. Zinc mediates its effects through two mechanisms; early zinc signaling (EZS) and late zinc signaling (LZS) [6]. LZS occurs several hours after an extracellular signaling event and depends on changes in the expression of zinc-related molecules such as zinc transporters and metallothioneins [6,7]. In contrast, EZS occurs minutes after an extracellular stimulus and does not involve transcriptional-dependent changes [6,7]. Zinc signaling mechanisms are involved in eliciting an increase in intracellular zinc concentrations 2 the zinc wave phenomenon [8]. Thus, in this situation zinc acts as a second messenger that activates pathways associated with cellular signaling. In fact, zinc has been categorized as an insulin-mimetic with several groups examining the role of its mimetic activity on glucose [913] and lipid [13,14] metabolism. In this context ZIP7 has been identified as a key zinc transporter implicated in the zinc wave and is suggested to be a gatekeeper of cytosolic zinc release from the ER [8]. Endogenous ZIP7 is predominately localized to the Golgi apparatus [15], the ER [16], or both [17] and has been implicated in breast cancer progression [8,17,18]. Studies in tamoxifen-resistant MCF-7 breast cancer cells identified that ZIP7 was responsible for activation of multiple tyrosine kinases that are implicated in the aggressive phenotype of tamoxifen-resistant b (...truncated)


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Stephen A. Myers, Alex Nield, Guat-Siew Chew, Mark A. Myers. The Zinc Transporter, Slc39a7 (Zip7) Is Implicated in Glycaemic Control in Skeletal Muscle Cells, PLOS ONE, 2013, 11, DOI: 10.1371/journal.pone.0079316