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Science 325 (5942): 877-880

Copyright © 2009 by the American Association for the Advancement of Science

ER Stress Controls Iron Metabolism Through Induction of Hepcidin

Chiara Vecchi,1 Giuliana Montosi,1 Kezhong Zhang,2 Igor Lamberti,1 Stephen A. Duncan,3 Randal J. Kaufman,4 Antonello Pietrangelo1,*

Abstract: 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.

1 Center for Hemochromatosis, Department of Internal Medicine, University Hospital Policlinico di Modena, Modena, Italy.
2 Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
3 Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
4 Howard Hughes Medical Institute, Departments of Biological Chemistry and Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109–0650, USA.

* To whom correspondence should be addressed. E-mail: antonello.pietrangelo{at}

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T. Sonnweber, D. Nachbaur, A. Schroll, M. Nairz, M. Seifert, E. Demetz, D. Haschka, A.-M. Mitterstiller, A. Kleinsasser, M. Burtscher, et al. (2014)
   Abstract »    Full Text »
Unfolded Protein Response Signaling and Metabolic Diseases.
J. Lee and U. Ozcan (2014)
J. Biol. Chem. 289, 1203-1211
   Abstract »    Full Text »    PDF »
Systemic Iron Homeostasis.
T. Ganz (2013)
Physiol Rev 93, 1721-1741
   Abstract »    Full Text »    PDF »
Xenobiotic Perturbation of ER Stress and the Unfolded Protein Response.
M. A. Lafleur, J. L. Stevens, and J. W. Lawrence (2013)
Toxicol Pathol 41, 235-262
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Hepcidin and the Iron-Infection Axis.
H. Drakesmith and A. M. Prentice (2012)
Science 338, 768-772
   Abstract »    Full Text »    PDF »
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D. Chanda, Y.-H. Kim, D.-K. Kim, M.-W. Lee, S.-Y. Lee, T.-S. Park, S.-H. Koo, C.-H. Lee, and H.-S. Choi (2012)
J. Biol. Chem. 287, 38041-38049
   Abstract »    Full Text »    PDF »
Acute Acetaminophen Intoxication Leads to Hepatic Iron Loading by Decreased Hepcidin Synthesis.
R. P. L. van Swelm, C. M. M. Laarakkers, L. Blous, J. G. P. Peters, E. N. B. Davidson, P. M. van der Kraan, D. W. Swinkels, R. Masereeuw, and F. G. M. Russel (2012)
Toxicol. Sci. 129, 225-233
   Abstract »    Full Text »    PDF »
The impact of the unfolded protein response on human disease.
S. Wang and R. J. Kaufman (2012)
J. Cell Biol. 197, 857-867
   Abstract »    Full Text »    PDF »
Pretreatment with CO-releasing molecules suppresses hepcidin expression during inflammation and endoplasmic reticulum stress through inhibition of the STAT3 and CREBH pathways.
D.-Y. Shin, J. Chung, Y. Joe, H.-O. Pae, K. C. Chang, G. J. Cho, S. W. Ryter, and H.-T. Chung (2012)
Blood 119, 2523-2532
   Abstract »    Full Text »    PDF »
Curcumin Differentially Regulates Endoplasmic Reticulum Stress through Transcriptional Corepressor SMILE (Small Heterodimer Partner-interacting Leucine Zipper Protein)-mediated Inhibition of CREBH (cAMP Responsive Element-binding Protein H).
J. Misra, D. Chanda, D.-k. Kim, T. Li, S.-H. Koo, S.-H. Back, J. Y. L. Chiang, and H.-S. Choi (2011)
J. Biol. Chem. 286, 41972-41984
   Abstract »    Full Text »    PDF »
Unraveling Mechanisms Regulating Systemic Iron Homeostasis.
K. E. Finberg (2011)
Hematology 2011, 532-537
   Abstract »    Full Text »    PDF »
Hepcidin in Human Iron Disorders: Diagnostic Implications.
J. J. C. Kroot, H. Tjalsma, R. E. Fleming, and D. W. Swinkels (2011)
Clin. Chem. 57, 1650-1669
   Abstract »    Full Text »    PDF »
Pathways for the regulation of hepcidin expression in anemia of chronic disease and iron deficiency anemia in vivo.
I. Theurl, A. Schroll, M. Nairz, M. Seifert, M. Theurl, T. Sonnweber, H. Kulaksiz, and G. Weiss (2011)
Haematologica 96, 1761-1769
   Abstract »    Full Text »    PDF »
Friend of GATA suppresses the GATA-induced transcription of hepcidin in hepatocytes through a GATA-regulatory element in the HAMP promoter.
E. T. Bagu and M. M. Santos (2011)
J. Mol. Endocrinol. 47, 299-313
   Abstract »    Full Text »    PDF »
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D. Chanda, D.-K. Kim, T. Li, Y.-H. Kim, S.-H. Koo, C.-H. Lee, J. Y. L. Chiang, and H.-S. Choi (2011)
J. Biol. Chem. 286, 27971-27979
   Abstract »    Full Text »    PDF »
Codanin-1 mutations in congenital dyserythropoietic anemia type 1 affect HP1{alpha} localization in erythroblasts.
R. Renella, N. A. Roberts, J. M. Brown, M. De Gobbi, L. E. Bird, T. Hassanali, J. A. Sharpe, J. Sloane-Stanley, D. J. P. Ferguson, J. Cordell, et al. (2011)
Blood 117, 6928-6938
   Abstract »    Full Text »    PDF »
The signalling from endoplasmic reticulum-resident bZIP transcription factors involved in diverse cellular physiology.
R. Asada, S. Kanemoto, S. Kondo, A. Saito, and K. Imaizumi (2011)
J. Biochem. 149, 507-518
   Abstract »    Full Text »    PDF »
Mutant HFE H63D Protein Is Associated with Prolonged Endoplasmic Reticulum Stress and Increased Neuronal Vulnerability.
Y. Liu, S. Y. Lee, E. Neely, W. Nandar, M. Moyo, Z. Simmons, and J. R. Connor (2011)
J. Biol. Chem. 286, 13161-13170
   Abstract »    Full Text »    PDF »
Iron in the inflammed gut: another pro-inflammatory hit?.
G. Weiss (2011)
Gut 60, 287-288
   Full Text »    PDF »
Hepcidin induction by transgenic overexpression of Hfe does not require the Hfe cytoplasmic tail, but does require hemojuvelin.
P. J. Schmidt, N. C. Andrews, and M. D. Fleming (2010)
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N-linked glycosylation is required for optimal proteolytic activation of membrane-bound transcription factor CREB-H.
C.-P. Chan, T.-Y. Mak, K.-T. Chin, I. O.-L. Ng, and D.-Y. Jin (2010)
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