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ER Stress Controls Iron Metabolism Through Induction of Hepcidin
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Hepcidin is a peptide hormone that is secreted by the liver and controls body iron homeostasis. Hepcidin overproduction causes anemia of inflammation, whereas its deficiency leads to hemochromatosis. Inflammation and iron are known extracellular stimuli for hepcidin expression. We found that endoplasmic reticulum (ER) stress also induces hepcidin expression and causes hypoferremia and spleen iron sequestration in mice. CREBH (cyclic AMP response element-binding protein H), an ER stress-activated transcription factor, binds to and transactivates the hepcidin promoter. Hepcidin induction in response to exogenously administered toxins or accumulation of unfolded protein in the ER is defective in CREBH knockout mice, indicating a role for CREBH in ER stress-regulated hepcidin expression. The regulation of hepcidin by ER stress links the intracellular response involved in protein quality control to innate immunity and iron homeostasis.
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“Cytokines such as interleukin (IL)-1, IL-6, or IL-22 as well as bacterial LPS or endoplasmic reticulum stress induce the formation of the master regulator of iron homeostasis, hepcidin, in the liver (Nemeth et al., 2003; Vecchi et al., 2009; Armitage et al., 2011).”
From Iron at the interface of immunity and infection (2014) · cites this paper as Vecchi et al., 2009
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Effects of excess dietary iron and fat on glucose and lipid metabolism
Choi, J. S., Koh, I.-U., Lee, H., Kim, W., & Song, J. (2013) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2013.02.004 · Cited by 83
Prasanthi, J. R. P., Larson, T., Schommer, J., & Ghribi, O. (2011) · PLoS ONE · doi:10.1371/journal.pone.0026420 · Cited by 80
“Gadd153 (also called CHOP) is activated by endoplasmic reticulum (ER) stress and can cause cellular damage by mechanisms that include induction of oxidative stress, generation of reactive oxygen species (ROS), triggering of apoptosis, and disturbing iron homeostasis [3–5].”
RetractedHepcidin messenger RNA expression in human lymphocytes
Pinto, J. P., Dias, V., Zoller, H., Porto, G., Carmo, H., Carvalho, F. D., & de Sousa, M. A. B. (2010) · Immunology · doi:10.1111/j.1365-2567.2009.03226.x · Cited by 81
Kushner, I., Samols, D. R., & Magrey, M. (2010) · Arthritis Care & Research · doi:10.1002/acr.20052 · Cited by 80
“specific CREB (structurally similar to ATF-6) ensues in the liver, with induction of CRP and of hepcidin, another acute-phase reactant, even in the absence of interleukin-6 stimulation (15,17).”
BackgroundTranscriptional regulators of hepatic gluconeogenesis
Oh, K., Han, H.-S., Kim, M.-J., & Koo, S. (2013) · Archives of Pharmacal Research · doi:10.1007/s12272-013-0018-5 · Cited by 80
Theurl, I., Schroll, A., Nairz, M., Seifert, M., Theurl, M., Sonnweber, T., Kulaksiz, H., & Weiss, G. (2011) · Haematologica · doi:10.3324/haematol.2011.048926 · Cited by 77
“7 In addition to iron and inflammation, the expression of hepcidin is controlled by hypoxia, endoplasmatic reticulum stress, erythropoietic activity and erythropoiesis driven signals (25, 35-40).”
BackgroundControl of the Unfolded Protein Response in Health and Disease
Doultsinos, D., Avril, T., Lhomond, S., Dejeans, N., Guédat, P., & Chevet, É. (2017) · SLAS DISCOVERY · doi:10.1177/2472555217701685 · Cited by 78
“Another example is provided by CREBH, whose activation upon ER stress was shown to control iron regulation in the liver through the control of hepcidin expression.(56) More recently, the AAA+ ATPase CDC48(yeast)/valosin-containing protein (VCP)/p97(mammals), known to play a role in ERAD,(57) was shown to also regulate…”
BackgroundLiu, C., Su, G., Giesy, J. P., Letcher, R. J., Li, G., Agrawal, I., Li, J., Yu, L., Wang, J., & Gong, Z. (2016) · Scientific Reports · doi:10.1038/srep19045 · Cited by 74
“Moreover, ER stress can directly induce TLRs and synergise with TLRs to cause inflammatory responses or/and related diseases in the liver 35,41–45 .”
Gáll, T., Balla, G., & Balla, J. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20153675 · Cited by 73
“Remarkably, ER stress upregulates hepcidin expression [123].”
Rath, E., & Haller, D. (2011) · European Journal of Nutrition · doi:10.1007/s00394-011-0197-0 · Cited by 75
“Of note, also luminal iron was shown to impact the composition of the intestinal microbiota as well as epithelial ER UPR [156], and concomitant CREBH and CHOP have been implicated in iron metabolism through regulation of the peptide hormone hepcidin [ 157 ].”
BackgroundMutual interaction between iron homeostasis and obesity pathogenesis
Nikonorov, A. А., Геннадиевна, С. М., Tinkov, A. A., & Skalny, A. V. (2014) · Journal of Trace Elements in Medicine and Biology · doi:10.1016/j.jtemb.2014.05.005 · Cited by 77
Iron and liver cancer: an inseparable connection
Hino, K., Yanatori, I., Hara, Y., & Nishina, S. (2021) · FEBS Journal · doi:10.1111/febs.16208 · Cited by 68
Mayeur, C., Isbell, L. K., Leyton, P., Kao, S. M., Pappas, A. E., Kolodziej, S. A., Spagnolli, E., Yu, B., Galdos, R. L., Yu, P. B., et al. (2014) · Blood · doi:10.1182/blood-2013-02-480095 · Cited by 75
The Potential for Transition Metal-Mediated Neurodegeneration in Amyotrophic Lateral Sclerosis
Lovejoy, D. B., & Guillemin, G. J. (2014) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2014.00173 · Cited by 66
“These studies were the first to demonstrate the reciprocal relationship between Fe homeostasis and ER stress, describing Hp induction as a marker of ER stress (Vecchi et al., 2009).”
BackgroundMayr, R., Griffiths, W. J. H., Hermann, M., McFarlane, I., Halsall, D. J., Finkenstedt, A., Douds, A., Davies, S. E., Janecke, A. R., Vogel, W., et al. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.02.064 · Cited by 64
Chan, C., Kok, K., & Jin, D. (2011) · Cell & Bioscience · doi:10.1186/2045-3701-1-6 · Cited by 64
“In addition to acute phase response genes such as the ones encoding C-reactive protein and amyloid P-component, several other important genes such as those of hepcidin, phosphoenolpyruvate carboxykinase and glucose 6 phosphatase were also direct targets of CREB3L3 [24,25].”
BackgroundSaito, A., & Imaizumi, K. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19103215 · Cited by 62
Chanda, D., Kim, D., Li, T., Kim, Y., Koo, S., Lee, C., Chiang, J. Y. L., & Choi, H. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.224352 · Cited by 63
Expression and function of iron‐regulatory proteins in retina
Gnana‐Prakasam, J. P., Martin, P. M., Smith, S. B., & Ganapathy, V. (2010) · IUBMB Life · doi:10.1002/iub.326 · Cited by 62
“CREBH (cyclic AMP response element-binding protein H), an endoplasmic reticulum (ER) stress-activated transcription factor, binds and transactivates the hepcidin promoter, thus linking the intracellular response involved in protein quality control to innate immunity and iron homeostasis (29).”
BackgroundUncoupled iron homeostasis in type 2 diabetes mellitus
Altamura, S., Kopf, S., Schmidt, J., Müdder, K., da Silva, A. R., Nawroth, P. P., & Muckenthaler, M. U. (2017) · Journal of Molecular Medicine · doi:10.1007/s00109-017-1596-3 · Cited by 65
Vela, D. (2018) · Molecular Medicine · doi:10.1186/s10020-018-0008-7 · Cited by 65
“(CREBH) and C/EBPα activity) is responsible for induction of hepcidin expression (Vecchi et al. 2009; Oliveira et al. 2009).”
BackgroundSaito, A., Kanemoto, S., Zhang, Y., Asada, R., Hino, K., & Imaizumi, K. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.11.008 · Cited by 63
“Recent studies have shown that UPR signaling is involved not only in dealing with unfolded proteins but also in biological regulation, including development and differentiation (Reimold et al., 2001; Zhang et al., 2006; Vecchi et al., 2009).”
BackgroundCorradini, E., & Pietrangelo, A. (2012) · Journal of Gastroenterology and Hepatology · doi:10.1111/j.1440-1746.2011.07014.x · Cited by 61
Self-citationAlterations in the redox state and liver damage: Hints from the EASL Basic School of Hepatology
Tell, G., Vascotto, C., & Tiribelli, C. (2012) · Journal of Hepatology · doi:10.1016/j.jhep.2012.09.018 · Cited by 61
“Finally, the complex interplay between iron, ROS, and ERS response was emphasized by the evidence that accumulation of unfolded proteins in ER induces hepcidin expression via the ERS response [101], thus linking ERS to iron homeostasis.”
BackgroundLee, H., Choi, J. S., Lee, H. J., Kim, W., Park, S. I., & Song, J. (2015) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2015.07.008 · Cited by 60
“element-binding protein H, which activate the hepcidin promoter and increase hepcidin expression [13].”
BackgroundErythropoietin's inhibiting impact on hepcidin expression occurs indirectly
Gammella, E., Diaz, V., Recalcati, S., Buratti, P., Samaja, M., Dey, S., Noguchi, C. T., Gassmann, M., & Cairo, G. (2015) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00410.2014 · Cited by 59
“Moreover, hepcidin expression is induced by inflammation (12), endoplasmic reticulum stress (21), and starvation (20).”
Iron regulates myeloma cell/macrophage interaction and drives resistance to bortezomib
Camiolo, G., Barbato, A., Giallongo, C., Vicario, N., Romano, A., Parrinello, N. L., Parenti, R., Cantón-Sandoval, J., García‐Moreno, D., Lazzarino, G., et al. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101611 · Cited by 60
Metadata
- Authors
- Vecchi, C., Montosi, G., Zhang, K., Lamberti, I., Duncan, S. A., Kaufman, R. J., & Pietrangelo, A.
- Affiliations
- Azienda Ospedaliero-Universitaria di Modena (IT)
- Wayne State University (US)
- Medical College of Wisconsin (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Pietrangelo, Antonello
- Venue
- Science
- Published
- 2009-08-14
- Volume
- 325
- Issue
- 5942
- Pages
- 877-880
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC2923557
- OpenAlex
- W2017168923
- Cited by
- 310
- References
- 26
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 5 · 2023: 14 · 2022: 8 · 2021: 16 · 2020: 15 · 2019: 11 · 2018: 20 · 2017: 18 · 2016: 19 · 2015: 30 · 2014: 27 · 2013: 28 · 2012: 30
- FWCI
- 19.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- Funders
- Howard Hughes Medical Institute
- National Heart, Lung, and Blood Institute (HL 52173, R01HL052173, P01HL057346)
- National Institute of Mental Health (R03MH089782)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK042394, DK42394, R37DK042394)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Keywords
- endoplasmic reticulum stress, hepcidin, iron homeostasis, CREBH, unfolded protein response, protein quality control, innate immunity, hypoferremia, anemia of chronic disease, hemochromatosis, transcriptional regulation
- MeSH terms
- Animals, Endoplasmic Reticulum, Homeostasis, Humans, Immunity, Innate, Iron, Liver, Mutation, Promoter Regions, Genetic, Spleen, Stress, Physiological, Transcriptional Activation, 3T3 Cells, Cyclic AMP Response Element-Binding Protein, Protein Folding, Mice, Knockout, Antimicrobial Cationic Peptides, RNA Interference, Cell Line, Tumor, Mice, Hepcidins
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