The zinc transporter Zip14 (SLC39a14) affects Beta-cell Function: Proteomics, Gene expression, and Insulin secretion studies in INS-1E cells

Abstract

Insulin secretion from pancreatic beta-cells is dependent on zinc ions as essential components of insulin crystals, zinc transporters are thus involved in the insulin secretory process. Zip14 (SLC39a14) is a zinc importing protein that has an important role in glucose homeostasis. Zip14 knockout mice display hyperinsulinemia and impaired insulin secretion in high glucose conditions. Endocrine roles for Zip14 have been established in adipocytes and hepatocytes, but not yet confirmed in beta-cells. In this study, we investigated the role of Zip14 in the INS-1E beta-cell line. Zip14 mRNA was upregulated during high glucose stimulation and Zip14 silencing led to increased intracellular insulin content. Large-scale proteomics showed that Zip14 silencing down-regulated ribosomal mitochondrial proteins, many metal-binding proteins, and others involved in oxidative phosphorylation and insulin secretion. Furthermore, proliferation marker Mki67 was down-regulated in Zip14 siRNA-treated cells. In conclusion, Zip14 gene expression is glucose sensitive and silencing of Zip14 directly affects insulin processing in INS-1E beta-cells. A link between Zip14 and ribosomal mitochondrial proteins suggests altered mitochondrial RNA translation, which could disturb mitochondrial function and thereby insulin secretion. This highlights a role for Zip14 in beta-cell functioning and suggests Zip14 as a future pharmacological target in the treatment of beta-cell dysfunction.

Iron Metabolism in Pancreatic Beta-Cell Function and Dysfunction

“…In primary human islets, NTBI uptake is mediated by the zinc transporter ZIP14 (SLC39A14), which localises to the plasma membrane of beta-cells, where iron loading is restricted. Chronic (24 h) high glucose levels upregulate the transporter expression, thus confirming the functional relevance of ZIP14 and suggesting possible consequences in iron homeostasis [ 34 ]. However, siRNA-mediated ZIP14 knockdown determined only a 50% reduction of NTBI uptake, suggesting that other transport systems may be involved as well.…”

“…Iron also directly controls ATP synthesis because, as an Fe-S cluster protein, it is part of the complexes I, II, III and IV of the mitochondrial respiratory chain. In line with this possibility, in the Ins-1E-β-cell line, ZIP14 silencing decreases iron transport into the cells and downregulates the expression of many metal-binding proteins, such as the cytoplasmic iron-sensing protein aconitase 1 (ACO1) and ribosomal mitochondrial proteins, thus affecting oxidative phosphorylation and insulin release [ 34 ].…”

Zinc ameliorates human aortic valve calcification through GPR39 mediated ERK1/2 signalling pathway

“…Consistent with this, knockdown of ZIP13 reduced osteogenic gene MSX2 and ALPL mRNA expression in hVICs. ZIP14 is responsible for zinc uptake by cells 35 , and has been reported to be a critical regulator of glucose homeostasis and beta-cell function 35,36 . We found that knockdown of ZIP14 in hVICs attenuated calcium deposition.…”

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

“…Interestingly, the two zinc importers that showed changed expression in ZnT8 haploinsufficient cells were ZIP8 and ZIP14, which both have functions in the immune response [58,59]. ZIP14 expression has also been linked to insulin content, processing, and secretion in INS-1E β-cells [60]. Further, since ZnT8 expression is not restricted to β-cells [61,62], polymorphisms may induce effects systemically.…”