A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression
Open accessAbstract
Hereditary hemochromatosis, characterized by iron overload in multiple organs, is one of the most common genetic disorders among Caucasians. Hepcidin, which is synthesized in the liver, plays important roles in iron overload syndromes. Here, we show that a Cre-loxP-mediated liver-specific disruption of SMAD4 results in markedly decreased hepcidin expression and accumulation of iron in many organs, which is most pronounced in liver, kidney, and pancreas. Transcript levels of genes involved in intestinal iron absorption, including Dcytb, DMT1, and ferroportin, are significantly elevated in the absence of hepcidin. We demonstrate that ectopic overexpression of SMAD4 activates the hepcidin promoter and is associated with epigenetic modification of histone H3 to a transcriptionally active form. Moreover, transcriptional activation of hepcidin is abrogated in SMAD4-deficient hepatocytes in response to iron overload, TGF-beta, BMP, or IL-6. Our study uncovers a novel role of TGF-beta/SMAD4 in regulating hepcidin expression and thus intestinal iron transport and iron homeostasis.
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Loss of hepatic SMAD4 is associated with decreased hepcidin expression and increased duodenal expression of iron absorption genes, leading to iron overload.
“Its expression is positively controlled inter alia by SMAD4, and loss of hepatic SMAD4 is thus associated with dramatically decreased expression of hepcidin in liver and increased duodenal expression of a variety of genes involved in intestinal iron absorption, including Dcytb, DMT1 and ferroportin, leading to iron overload [346].”
Inactivation of SMAD4 exclusively in hepatocytes resulted in severe hemochromatosis similar to that seen in mice lacking hepcidin.
“In the course of their general studies of cellular signaling, Wang and colleagues inactivated the gene encoding an essential SMAD protein, SMAD4, exclusively in hepatocytes.113 To their surprise, the dominant phenotype that resulted was severe hemochromatosis, similar to that seen in mice lacking hepcidin.”
From Forging a field: the golden age of iron biology. (2008) · cites this paper as [113]
BMP treatment is a potent stimulus for hepcidin expression both in cultured cells and in animals.
“Nonetheless, BMP treatment is a potent stimulus for hepcidin expression both in cultured cells 113,114,116,117 and in animals.”
From Forging a field: the golden age of iron biology. (2008) · cites this paper as [113]
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- Authors
- Wang, R.-H., Li, C., Xu, X., Zheng, Y., Xiao, C., Zerfas, P., Cooperman, S., Eckhaus, M., Rouault, T., Mishra, L., & Deng, C.-X.
- Affiliations
- National Institutes of Health (US)
- National Institute of Diabetes and Digestive and Kidney Diseases (US)
- Office of Research Services (US)
- Georgetown University (US)
- Corresponding author
- Deng, Chu-Xia
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2005-12
- Volume
- 2
- Issue
- 6
- Pages
- 399-409
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2163487646
- Cited by
- 614
- References
- 58
- Citations by year
- 2026: 8 · 2025: 17 · 2024: 10 · 2023: 18 · 2022: 13 · 2021: 33 · 2020: 24 · 2019: 23 · 2018: 21 · 2017: 27 · 2016: 20 · 2015: 14 · 2014: 36 · 2013: 40 · 2012: 29
- FWCI
- 22.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- SMAD4, hepcidin, iron metabolism, iron homeostasis, hereditary hemochromatosis, iron overload, intestinal iron absorption, Dcytb, DMT1, ferroportin, TGF-beta signaling, BMP signaling, IL-6 signaling, hepatocytes
- MeSH terms
- Ferroportin, Solute Carrier Family 11, Member 2, Alleles, Animals, Biological Transport, Cloning, Molecular, Cytochrome b Group, Ferrocyanides, Fluorescent Dyes, Gene Expression Regulation, Histones, Immunohistochemistry, Intestinal Mucosa, Iron, Liver, Mice, Transgenic, Oxidoreductases, Promoter Regions, Genetic, Time Factors, Transcription, Genetic, Transcriptional Activation, Interleukin-6, Transforming Growth Factor beta, DNA Primers, Bone Morphogenetic Proteins, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Hepatocytes, Antimicrobial Cationic Peptides, Cation Transport Proteins, Iron-Binding Proteins, Chromatin Immunoprecipitation, Mice, Smad4 Protein, Hepcidins
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