The plasma membrane metal-ion transporter ZIP14 contributes to nontransferrin-bound iron uptake by human β-cells

Am J Physiol Cell Physiol. 2017 Feb 1;312(2):C169-C175. doi: 10.1152/ajpcell.00116.2016. Epub 2016 Nov 30.

Abstract

The relationship between iron and β-cell dysfunction has long been recognized as individuals with iron overload display an increased incidence of diabetes. This link is usually attributed to the accumulation of excess iron in β-cells leading to cellular damage and impaired function. Yet, the molecular mechanism(s) by which human β-cells take up iron has not been determined. In the present study, we assessed the contribution of the metal-ion transporters ZRT/IRT-like protein 14 and 8 (ZIP14 and ZIP8) and divalent metal-ion transporter-1 (DMT1) to iron uptake by human β-cells. Iron was provided to the cells as nontransferrin-bound iron (NTBI), which appears in the plasma during iron overload and is a major contributor to tissue iron loading. We found that overexpression of ZIP14 and ZIP8, but not DMT1, resulted in increased NTBI uptake by βlox5 cells, a human β-cell line. Conversely, siRNA-mediated knockdown of ZIP14, but not ZIP8, resulted in 50% lower NTBI uptake in βlox5 cells. In primary human islets, knockdown of ZIP14 also reduced NTBI uptake by 50%. Immunofluorescence analysis of islets from human pancreatic sections localized ZIP14 and DMT1 nearly exclusively to β-cells. Studies in primary human islets suggest that ZIP14 protein levels do not vary with iron status or treatment with IL-1β. Collectively, these observations identify ZIP14 as a major contributor to NTBI uptake by β-cells and suggest differential regulation of ZIP14 in primary human islets compared with other cell types such as hepatocytes.

Keywords: ZIP14; diabetes; hemochromatosis; iron; β-cell.

MeSH terms

  • Cation Transport Proteins / metabolism*
  • Cell Line
  • Cell Membrane / metabolism*
  • Cells, Cultured
  • Humans
  • Insulin-Secreting Cells / metabolism*
  • Ion Channel Gating / physiology*
  • Iron / pharmacokinetics*
  • Transcription Factors / metabolism
  • Transferrin / metabolism*

Substances

  • Cation Transport Proteins
  • DMRT1 protein
  • SLC39A14 protein, human
  • Transcription Factors
  • Transferrin
  • Zip8 protein, human
  • Iron