SLC39A14 Is Required for the Development of Hepatocellular Iron Overload in Murine Models of Hereditary Hemochromatosis

Cell Metab. 2015 Jul 7;22(1):138-50. doi: 10.1016/j.cmet.2015.05.002. Epub 2015 May 28.

Abstract

Nearly all forms of hereditary hemochromatosis are characterized by pathological iron accumulation in the liver, pancreas, and heart. These tissues preferentially load iron because they take up non-transferrin-bound iron (NTBI), which appears in the plasma during iron overload. Yet, how tissues take up NTBI is largely unknown. We report that ablation of Slc39a14, the gene coding for solute carrier SLC39A14 (also called ZIP14), in mice markedly reduced the uptake of plasma NTBI by the liver and pancreas. To test the role of SLC39A14 in tissue iron loading, we crossed Slc39a14(-/-) mice with Hfe(-/-) and Hfe2(-/-) mice, animal models of type 1 and type 2 (juvenile) hemochromatosis, respectively. Slc39a14 deficiency in hemochromatotic mice greatly diminished iron loading of the liver and prevented iron deposition in hepatocytes and pancreatic acinar cells. The data suggest that inhibition of SLC39A14 may mitigate hepatic and pancreatic iron loading and associated pathologies in iron overload disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism*
  • Cells, Cultured
  • Female
  • Gene Deletion
  • Hemochromatosis / complications
  • Hemochromatosis / congenital*
  • Hemochromatosis / genetics
  • Hemochromatosis / metabolism
  • Hemochromatosis / pathology
  • Hepatocytes / metabolism
  • Hepatocytes / pathology*
  • Iron Overload / complications
  • Iron Overload / genetics
  • Iron Overload / metabolism*
  • Iron Overload / pathology
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice, Inbred C57BL
  • Pancreas / metabolism
  • Pancreas / pathology

Substances

  • Cation Transport Proteins
  • SLC39A14 protein, mouse

Supplementary concepts

  • Hemochromatosis, type 2