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

Junwei Gao, Ningning Zhao, Mitchell D. Knutson, Caroline Enns

Research output: Contribution to journalArticle

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Abstract

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 ∼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.

Original languageEnglish (US)
Pages (from-to)21462-21468
Number of pages7
JournalJournal of Biological Chemistry
Volume283
Issue number31
DOIs
StatePublished - Aug 1 2008

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Hep G2 Cells
Down-Regulation
Iron
Proteins
Transferrin
Cells
Cell Line
Iron Overload
Hemochromatosis Protein
Tetracycline
HeLa Cells
Small Interfering RNA
Half-Life
Hepatocytes
Hepatocellular Carcinoma
Liver
Metals
Messenger RNA

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

The hereditary hemochromatosis protein, HFE, inhibits iron uptake via down-regulation of Zip14 in HepG2 Cells. / Gao, Junwei; Zhao, Ningning; Knutson, Mitchell D.; Enns, Caroline.

In: Journal of Biological Chemistry, Vol. 283, No. 31, 01.08.2008, p. 21462-21468.

Research output: Contribution to journalArticle

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