title: The plasma membrane metal-ion transporter ZIP14 contributes to nontransferrin-bound iron uptake by human β-cells.
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.
authors.affiliation: Food Science and Human Nutrition Department, University of Florida, Gainesville, Florida.
authors.forename: Richard
authors.initials: R
authors.lastname: Coffey
authors.affiliation: Food Science and Human Nutrition Department, University of Florida, Gainesville, Florida mknutson@ufl.edu.
authors.forename: Mitchell D
authors.initials: MD
authors.lastname: Knutson
mesh_terms: D027682:Cation Transport Proteins / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D015640:Ion Channel Gating / Q000502:physiology*; D007501:Iron / Q000493:pharmacokinetics*; D014157:Transcription Factors / Q000378:metabolism; D014168:Transferrin / Q000378:metabolism*
chemical_list: D027682:Cation Transport Proteins; C110547:DMRT1 protein; C497524:SLC39A14 protein, human; C530151:SLC39A8 protein, human; D014157:Transcription Factors; D014168:Transferrin; D007501:Iron
keywords: ZIP14; diabetes; hemochromatosis; iron; β-cell