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Article

ZnT8 Haploinsufficiency Impacts MIN6 Cell Zinc Content and β-Cell Phenotype via ZIP-ZnT8 Coregulation

Metal Metabolism Group, Department of Nutritional Sciences, Faculty of Life Sciences and Medicine, King’s College London, 150 Stamford St, London SE1 9NH, UK
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Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(21), 5485; https://doi.org/10.3390/ijms20215485
Received: 13 September 2019 / Revised: 28 October 2019 / Accepted: 29 October 2019 / Published: 4 November 2019
(This article belongs to the Special Issue Advances in Metal Metabolism Research)
The zinc transporter ZnT8 (SLC30A8) localises to insulin secretory granules of β-cells where it facilitates zinc uptake for insulin crystallisation. ZnT8 abundance has been linked to β-cell survival and functional phenotype. However, the consequences of ZnT8 haploinsufficiency for β-cell zinc trafficking and function remain unclear. Since investigations in human populations have shown SLC30A8 truncating polymorphisms to decrease the risk of developing Type 2 Diabetes, we hypothesised that ZnT8 haploinsufficiency would improve β-cell function and maintain the endocrine phenotype. We used CRISPR/Cas9 technology to generate ZnT8 haploinsufficient mouse MIN6 β-cells and showed that ZnT8 haploinsufficiency is associated with downregulation of mRNAs for Slc39a8 and Slc39a14, which encode for the zinc importers, Znt- and Irt-related proteins 8 (ZIP8) and 14 (ZIP14), and with lowered total cellular zinc content. ZnT8 haploinsufficiency disrupts expression of a distinct array of important β-cell markers, decreases cellular proliferation via mitogen-activated protein (MAP) kinase cascades and downregulates insulin gene expression. Thus, ZnT8 cooperates with zinc importers of the ZIP family to maintain β-cell zinc homeostasis. In contrast to the hypothesis, lowered ZnT8 expression reduces MIN6 cell survival by affecting zinc-dependent transcription factors that control the β-cell phenotype. View Full-Text
Keywords: ZnT8; ZIP; zinc; MIN6 cells; β-cells; Type 2 Diabetes ZnT8; ZIP; zinc; MIN6 cells; β-cells; Type 2 Diabetes
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MDPI and ACS Style

Lawson, R.; Maret, W.; Hogstrand, C. ZnT8 Haploinsufficiency Impacts MIN6 Cell Zinc Content and β-Cell Phenotype via ZIP-ZnT8 Coregulation. Int. J. Mol. Sci. 2019, 20, 5485. https://doi.org/10.3390/ijms20215485

AMA Style

Lawson R, Maret W, Hogstrand C. ZnT8 Haploinsufficiency Impacts MIN6 Cell Zinc Content and β-Cell Phenotype via ZIP-ZnT8 Coregulation. International Journal of Molecular Sciences. 2019; 20(21):5485. https://doi.org/10.3390/ijms20215485

Chicago/Turabian Style

Lawson, Rebecca, Wolfgang Maret, and Christer Hogstrand. 2019. "ZnT8 Haploinsufficiency Impacts MIN6 Cell Zinc Content and β-Cell Phenotype via ZIP-ZnT8 Coregulation" International Journal of Molecular Sciences 20, no. 21: 5485. https://doi.org/10.3390/ijms20215485

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