Regulation of growth differentiation factor 15 expression by intracellular iron
Abstract
Growth differentiation factor 15 (GDF15) is a divergent member of the transforming growth factor-beta superfamily and has been identified in different contexts as a hypoxia-inducible gene product and as a molecule involved in hepcidin regulation. The biology of iron and oxygen is closely related, and known regulatory pathways involving hypoxia-inducible factor (HIF) and iron-regulatory proteins (IRPs) are responsive to both these stimuli. We therefore sought to characterize the regulation of GDF15 by iron and oxygen and to define the involvement or otherwise of HIF and IRP pathways. Here we show that GDF15 is strongly up-regulated by stimuli that deplete cells of iron and that this response is specifically antagonized by the reprovision of iron. GDF15 exhibits greater sensitivity to iron depletion than hypoxia, and responses to hypoxia and iron depletion are independent of HIF and IRP activation, suggesting a novel mechanism of regulation. We also report significant induction of serum GDF15 in iron-deficient subjects and after administration of an iron chelator to normal subjects. These findings indicate that GDF15 can be induced by pathophysiologic changes in iron availability, raising important questions about the mechanism of regulation and its role in iron homeostasis.
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GDF15 is an iron- and O2-regulated (HIF-independent) member of the TGF-β superfamily, secreted from maturing erythroblasts, and has been shown to suppress hepcidin transcription in primary human hepatocytes and hepatoma cells.
“GDF15 is an iron- and O2-regulated (HIF-independent) member of the TGF-β superfamily, which is secreted from maturing erythroblasts and has been shown to suppress hepcidin transcription in primary human hepatocytes and hepatoma cells”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [217]
Patients with low serum iron had elevated GDF15 levels compared to iron-replete controls (mean 1048 pg/ml vs. 542 pg/ml).
“Lakhal and colleagues reported that patients with low serum iron had elevated GDF15 levels compared to iron-replete controls (mean of 1048 pg/ml vs. 542 pg/ml).”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [217]
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- Authors
- Lakhal, S., Talbot, N. P., Crosby, A., Stoepker, C., Townsend, A. R. M., Robbins, P. A., Pugh, C. W., Ratcliffe, P. J., & Mole, D. R.
- Affiliations
- Henry Wellcome Building for Molecular Physiology and
- University of Oxford (GB)
- John Radcliffe Hospital (GB)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2009-02-12
- Volume
- 113
- Issue
- 7
- Pages
- 1555-1563
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2016849042
- Cited by
- 95
- References
- 47
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2023: 5 · 2021: 12 · 2020: 8 · 2019: 2 · 2017: 3 · 2016: 3 · 2015: 8 · 2014: 6 · 2013: 6 · 2012: 6
- FWCI
- 7.13
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- European Commission
- Topics
- Health Sciences › Medicine › Rheumatology › GDF15 and Related Biomarkers
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Keywords
- growth differentiation factor 15, GDF15, iron regulation, iron deficiency, hypoxia, hypoxia-inducible factor, iron regulatory proteins, iron homeostasis, hepcidin, oxygen sensing, iron chelation, gene expression regulation
- MeSH terms
- Hemochromatosis Protein, Ferroportin, Endothelial PAS Domain-Containing Protein 1, Adenocarcinoma, Breast Neoplasms, Deferoxamine, HeLa Cells, Carcinoma, Hepatocellular, Humans, Iron, Kidney, Kidney Neoplasms, Membrane Proteins, Oxygen, Transcription, Genetic, Histocompatibility Antigens Class I, Cell Hypoxia, Siderophores, Anemia, Iron-Deficiency, Cation Transport Proteins, Wnt2 Protein, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, alpha Subunit, Growth Differentiation Factor 15
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