Cited by 326Iron Metabolism and DisordersNeurological diseases and metabolismFerroptosis and cancer prognosis

Interaction of the Hereditary Hemochromatosis Protein HFE with Transferrin Receptor 2 Is Required for Transferrin-Induced Hepcidin Expression

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Gao, Junwei, Chen, Juxing, Kramer, Maxwell, Tsukamoto, Hidekazu, Zhang, An-Sheng, Enns, Caroline A.·2009·Cell Metabolism

Abstract

The mechanisms that allow the body to sense iron levels in order to maintain iron homeostasis are unknown. Patients with the most common form of hereditary iron overload have mutations in the hereditary hemochromatosis protein HFE. They have lower levels of hepcidin than unaffected individuals. Hepcidin, a hepatic peptide hormone, negatively regulates iron efflux from the intestines into the blood. We report two hepatic cell lines, WIF-B cells and HepG2 cells transfected with HFE, where hepcidin expression responded to iron-loaded transferrin. The response was abolished when endogenous transferrin receptor 2 (TfR2) was suppressed or in primary hepatocytes lacking either functional TfR2 or HFE. Furthermore, transferrin-treated HepG2 cells transfected with HFE chimeras containing only the alpha3 and cytoplasmic domains could upregulate hepcidin expression. Since the HFE alpha3 domain interacts with TfR2, these results supported our finding that TfR2/HFE complex is required for transcriptional regulation of hepcidin by holo-Tf.

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Crossref · 10.1016/j.cmet.2009.01.010

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  • Activation of signaling through HFE, TFR1, TFR2, or HJV increases hepcidin transcription in a SMAD-dependent fashion.

    “Activation of signaling through the hemochromatosis protein HFE, TFR1, TFR2, or hemojuvelin (HJV), which acts as a co-receptor for bone morphogenetic protein 6 (BMP6), increases hepcidin transcription in a SMAD-dependent fashion.”

    From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [198]

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Authors
Gao, J., Chen, J., Kramer, M., Tsukamoto, H., Zhang, A.-S., & Enns, C. A.
Affiliations
  • Oregon Health & Science University (US)
  • University of Southern California (US)
Corresponding author
Enns, Caroline A.
Venue
Cell Metabolism
Publisher
Elsevier BV
Published
2009-03
Volume
9
Issue
3
Pages
217-227
ISSN
1550-4131 (ISSN-L)
OpenAlex
W2079904892
Cited by
326
References
57
Citations by year
2026: 10 · 2025: 8 · 2024: 10 · 2023: 6 · 2022: 13 · 2021: 19 · 2020: 16 · 2019: 14 · 2018: 12 · 2017: 11 · 2016: 11 · 2015: 19 · 2014: 19 · 2013: 30 · 2012: 22
FWCI
27.77
Type
journal article
Language
en
Open access
Locations
  • Cell Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (AA011999, DK072166)
  • National Institute on Alcohol Abuse and Alcoholism (P50AA011999)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R37DK054488, R01DK072166, R01DK054488)
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
Keywords
hereditary hemochromatosis, HFE gene, transferrin receptor 2, hepcidin, iron homeostasis, iron overload, transferrin, transcriptional regulation, hepatocytes, iron sensing
MeSH terms
Hemochromatosis Protein, Animals, Cells, Cultured, Homeostasis, Humans, Iron, Liver, Membrane Proteins, Promoter Regions, Genetic, Receptors, Transferrin, Recombinant Fusion Proteins, Transferrin, Histocompatibility Antigens Class I, Antigens, CD, Mice, Knockout, Hepatocytes, Antimicrobial Cationic Peptides, RNA, Small Interfering, Mice, Hepcidins

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