The hereditary hemochromatosis protein, HFE, inhibits iron uptake via down-regulation of Zip14 in HepG2 cells

J Biol Chem. 2008 Aug 1;283(31):21462-8. doi: 10.1074/jbc.M803150200. Epub 2008 Jun 4.


Lack of functional hereditary hemochromatosis protein, HFE, causes iron overload predominantly in hepatocytes, the major site of HFE expression in the liver. In this study, we investigated the role of HFE in the regulation of both transferrin-bound iron (TBI) and non-transferrin-bound iron (NTBI) uptake in HepG2 cells, a human hepatoma cell line. Expression of HFE decreased both TBI and NTBI uptake. It also resulted in a decrease in the protein levels of Zip14 with no evident change in the mRNA level of Zip14. Zip14 (Slc39a14) is a metal transporter that mediates NTBI into cells (Liuzzi, J. P., Aydemir, F., Nam, H., Knutson, M. D., and Cousins, R. J. (2006) Proc. Natl. Acad. Sci. U. S. A. 103, 13612-13617). Knockdown of Zip14 with siRNA abolished the effect of HFE on NTBI uptake. To determine if HFE had a similar effect on Zip14 in another cell line, HeLa cells expressing HFE under the tetracycline-repressible promoter were transfected with Zip14. As in HepG2 cells, HFE expression inhibited NTBI uptake by approximately 50% and decreased Zip14 protein levels. Further analysis of protein turnover indicated that the half-life of Zip14 is lower in cells that express HFE. These results suggest that HFE decreases the stability of Zip14 and therefore reduces the iron loading in HepG2 cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cation Transport Proteins / chemistry*
  • Cell Line
  • Cell Line, Tumor
  • Down-Regulation
  • Gene Expression Regulation*
  • HeLa Cells
  • Hemochromatosis / metabolism*
  • Hemochromatosis / pathology
  • Hemochromatosis Protein
  • Histocompatibility Antigens Class I / metabolism
  • Histocompatibility Antigens Class I / physiology*
  • Humans
  • Iron / chemistry
  • Iron / metabolism
  • Iron / pharmacokinetics*
  • Membrane Proteins / metabolism
  • Membrane Proteins / physiology*
  • Promoter Regions, Genetic
  • RNA, Small Interfering / metabolism
  • Time Factors
  • Transferrin / chemistry


  • Cation Transport Proteins
  • HFE protein, human
  • Hemochromatosis Protein
  • Histocompatibility Antigens Class I
  • Membrane Proteins
  • RNA, Small Interfering
  • SLC39A14 protein, human
  • Transferrin
  • Iron