ER Stress Controls Iron Metabolism Through Induction of Hepcidin
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Cytokines such as interleukin (IL)-1, IL-6, or IL-22 as well as bacterial LPS or endoplasmic reticulum stress induce the formation of hepcidin in the liver.
“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
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Control of inositol 1,4,5-trisphosphate-induced Ca2+ release by cytosolic Ca2+
Bootman, M. D., Missiaen, L., Parys, J. B., SMEDT, H. D., & Casteels, R. (1995) · Biochemical Journal · doi:10.1042/bj3060445 · Cited by 5,120 · see citing works
Hepcidin Regulates Cellular Iron Efflux by Binding to Ferroportin and Inducing Its Internalization
Nemeth, E., Tuttle, M. S., Powelson, J., Vaughn, M. B., Donovan, A., Ward, D. M., Ganz, T., & Kaplan, J. (2004) · Science · doi:10.1126/science.1104742 · Cited by 4,803 · see citing works
Yoshida, H., Matsui, T., Yamamoto, A., Okada, T., & Mori, K. (2001) · Cell · doi:10.1016/s0092-8674(01)00611-0 · Cited by 4,054 · see citing works
Mutation of the mouse klotho gene leads to a syndrome resembling ageing
Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., et al. (1997) · Nature · doi:10.1038/36285 · Cited by 3,837 · see citing works
THE MAMMALIAN UNFOLDED PROTEIN RESPONSE
Schröder, M., & Kaufman, R. J. (2005) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.73.011303.074134 · Cited by 3,035 · see citing works
Self-citationPigeon, C., Ilyin, G., Courselaud, B., Leroyer, P., Turlin, B., Brissot, P., & Loréal, O. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m008923200 · Cited by 1,697 · see citing works
Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein
Nemeth, E., Valore, E. V., Territo, M., Schiller, G., Lichtenstein, A., & Ganz, T. (2003) · Blood · doi:10.1182/blood-2002-10-3235 · Cited by 1,417 · see citing works
Dysmetabolic Hyperferritinemia: All Iron Overload Is Not Hemochromatosis
Makker, J. S., Hanif, A., Bajantri, B., & Chilimuri, S. S. (2015) · Case Reports in Gastroenterology · doi:10.1159/000373883 · Cited by 1,353 · see citing works
Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression
Babitt, J. L., Huang, F. W., Wrighting, D. M., Xia, Y., Sidis, Y., Samad, T. A., Campagna, J. A., Chung, R. T., Schneyer, A. L., Woolf, C. J., et al. (2006) · Nature Genetics · doi:10.1038/ng1777 · Cited by 1,026 · see citing works
Hereditary Hemochromatosis — A New Look at an Old Disease
Pietrangelo, A. (2004) · New England Journal of Medicine · doi:10.1056/nejmra031573 · Cited by 992 · see citing works
Self-citationInterleukin-6 induces hepcidin expression through STAT3
Wrighting, D. M., & Andrews, N. C. (2006) · Blood · doi:10.1182/blood-2006-06-027631 · Cited by 983 · see citing works
From acute ER stress to physiological roles of the Unfolded Protein Response
Wu, J., & Kaufman, R. J. (2006) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401840 · Cited by 868 · see citing works
Self-citationEndoplasmic Reticulum Stress Activates Cleavage of CREBH to Induce a Systemic Inflammatory Response
Zhang, K., Shen, X., Wu, J., Sakaki, K., Saunders, T. L., Rutkowski, D. T., Back, S. H., & Kaufman, R. J. (2006) · Cell · doi:10.1016/j.cell.2005.11.040 · Cited by 819 · see citing works
Self-citationA role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression
Wang, R.-H., Li, C., Xu, X., Zheng, Y., Xiao, C., Zerfas, P., Cooperman, S., Eckhaus, M., Rouault, T., Mishra, L., et al. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.10.010 · Cited by 614 · see citing works
STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation
Verga Falzacappa, M. V., Vujic Spasic, M., Kessler, R., Stolte, J., Hentze, M. W., & Muckenthaler, M. U. (2007) · Blood · doi:10.1182/blood-2006-07-033969 · Cited by 567 · see citing works
Classification of Human B-ZIP Proteins Based on Dimerization Properties
Vinson, C., Myakishev-Rempel, M., Acharya, A., Mir, A. A., Moll, J. R., & Bonovich, M. T. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.18.6321-6335.2002 · Cited by 450 · see citing works
Nicolle, L. S. (1984) · The Nurse Practitioner · doi:10.1097/00006205-198411000-00004 · Cited by 416 · see citing works
(1994) · PubMed · Cited by 381 · see citing works
STAT3 Is Required for IL-6-gp130–Dependent Activation of Hepcidin In Vivo
Pietrangelo, A., Dierssen, U., Valli, L., Garuti, C., Rump, A., Corradini, E., Ernst, M., Klein, C., & Trautwein, C. (2007) · Gastroenterology · doi:10.1053/j.gastro.2006.10.018 · Cited by 315 · see citing works
Self-citationMuckenthaler, M. U., Roy, C. N., Custodio, Á. O., Miñana, B., DEGRAAF, J., Montross, L. K., Andrews, N. C., & Hentze, M. W. (2003) · Nature Genetics · doi:10.1038/ng1152 · Cited by 293 · see citing works
Courselaud, B., Pigeon, C., Inoue, Y., Inoue, J., Gonzalez, F. J., Leroyer, P., Gilot, D., Boudjema, K., Guguen-Guillouzo, C., Brissot, P., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m202653200 · Cited by 245 · see citing works
Bioengineering of coagulation factor VIII for improved secretion
Miao, H. Z., Sirachainan, N., Palmer, L. E., Kucab, P., Cunningham, M. A., Kaufman, R. J., & Pipe, S. W. (2004) · Blood · doi:10.1182/blood-2003-10-3591 · Cited by 209 · see citing works
Self-citationHepcidin—A Peptide Hormone at the Interface of Innate Immunity and Iron Metabolism
Ganz, T. (2006) · Springer eBooks · doi:10.1007/3-540-29916-5_7 · Cited by 146 · see citing works
The anemia of chronic disorders.
Cartwright, G. E. (1966) · PubMed · Cited by 115 · see citing works
In vivo imaging of hepcidin promoter stimulation by iron and inflammation
Flanagan, J. M., Truksa, J., Peng, H., Lee, P. L., & Beutler, E. (2007) · Blood Cells Molecules and Diseases · doi:10.1016/j.bcmd.2007.01.004 · Cited by 24 · see citing works
Flagged first, then by citations
1 of the 26 references couldn’t be matched to a known paper.
Research works printed but not linked: 2
- [3]Cartwright GE Semin. Hematol 1966 3 351 5341723
- [18]Hurst HC Protein Profile 1995 2 101 7780801
Cited by
Sorted by citations
The unfolded protein response: controlling cell fate decisions under ER stress and beyond
Hetz, C. A. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3270 · Cited by 4,118 · see citing works
“In addition, ER stress regulates the synthesis of the peptide hormone hepcidin”
BackgroundEndoplasmic reticulum stress and the inflammatory basis of metabolic disease
Hotamisligil, G. S. (2010) · Cell · doi:10.1016/j.cell.2010.02.034 · Cited by 2,802 · see citing works
“Both CREBH and CHOP may play a role in the regulation of the peptide hormone hepcidin, which may link iron metabolism to inflammatory output via the ER (Vecchi et al., 2009).”
Two to tango: Regulation of Mammalian iron metabolism
Hentze, M. W., Muckenthaler, M. U., Galy, B., & Camaschella, C. (2010) · Cell · doi:10.1016/j.cell.2010.06.028 · Cited by 2,120 · see citing works
Endoplasmic reticulum stress in liver disease
Malhi, H., & Kaufman, R. J. (2010) · Journal of Hepatology · doi:10.1016/j.jhep.2010.11.005 · Cited by 1,178 · see citing works
“Hepcidin, an iron regulatory hormone and an APR protein, is also induced by CREBH upon ER stress [137].”
BackgroundSelf-citationGanz, T. (2013) · Physiological Reviews · doi:10.1152/physrev.00008.2013 · Cited by 1,122 · see citing works
“Endoplasmic reticulum (ER) stress is a pathological signal that modulates hepcidin synthesis, via cAMP response element-binding protein H (CREBH), an ER stress-activated transcription factor and the stress-inducible transcription factor and through CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) (173,…”
BackgroundRegulation of cellular iron metabolism
Wang, J., & Pantopoulos, K. (2011) · Biochemical Journal · doi:10.1042/bj20101825 · Cited by 986 · see citing works
The impact of the unfolded protein response on human disease
Wang, S., & Kaufman, R. J. (2012) · The Journal of Cell Biology · doi:10.1083/jcb.201110131 · Cited by 983 · see citing works
“It was also reported that IRE1 indiscriminately degrades ER-localized mRNAs that can lead to cell death (Hollien et al., 2009; Vecchi et al., 2009).”
BackgroundSelf-citationEndoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease
Lebeaupin, C., Vallée, D., Hazari, Y., Hetz, C. A., Chevet, É., & Bailly‐Maitre, B. (2018) · Journal of Hepatology · doi:10.1016/j.jhep.2018.06.008 · Cited by 945 · see citing works
Targeting the unfolded protein response in disease
Hetz, C. A., Chevet, É., & Harding, H. P. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd3976 · Cited by 908 · see citing works
Iron homeostasis in host defence and inflammation
Ganz, T., & Nemeth, E. (2015) · Nature Reviews Immunology · doi:10.1038/nri3863 · Cited by 843 · see citing works
Hepcidin and the iron-infection axis
Drakesmith, H., & Prentice, A. M. (2012) · Science · doi:10.1126/science.1224577 · Cited by 686 · see citing works
Hereditary Hemochromatosis: Pathogenesis, Diagnosis, and Treatment
Pietrangelo, A. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.06.013 · Cited by 615 · see citing works
Self-citationRegulation of iron transport and the role of transferrin
Gkouvatsos, K., Papanikolaou, G., & Pantopoulos, K. (2012) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2011.10.013 · Cited by 518 · see citing works
Linking cellular stress responses to systemic homeostasis
Galluzzi, L., Yamazaki, T., & Kroemer, G. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0068-0 · Cited by 529 · see citing works
Anemia at older age: etiologies, clinical implications, and management
Stauder, R., Valent, P., & Theurl, I. (2018) · Blood · doi:10.1182/blood-2017-07-746446 · Cited by 479 · see citing works
Arroyo, V., Angeli, P., Moreau, R., Jalan, R., Clària, J., Trebicka, J., Fernández, J., Gustot, T., Caraceni, P., & Bernardi, M. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2020.11.048 · Cited by 479 · see citing works
“Another acute-phase protein is hepcidin, whose role is to limit the availability of iron, which is vital for invading microbes .(79) The liver is, therefore, a site of an extensive energyconsuming anabolic metabolism during systemic inflammation.”
BackgroundIron Homeostasis and the Inflammatory Response
Wessling-Resnick, M. (2010) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.012809.104804 · Cited by 480 · see citing works
“Activation of CREBH by UPR stress promotes expression of acute-phase response genes.”
BackgroundInfluentialIron in fatty liver and in the metabolic syndrome: A promising therapeutic target
Dongiovanni, P., Fracanzani, A. L., Fargion, S. R., & Valenti, L. V. C. (2011) · Journal of Hepatology · doi:10.1016/j.jhep.2011.05.008 · Cited by 360 · see citing works
“It is thus possible that the coexistence of multiple genetic variants contributes to DIOS [13,14,27,30], and it could be speculated that AAT modulate iron metabolism by inducing ER stress [58].”
BackgroundMultiple loci influence erythrocyte phenotypes in the CHARGE Consortium
Ganesh, S. K., Zakai, N. A., van Rooij, F. J. A., Soranzo, N., Smith, A. V., Nalls, M. A., Chen, M., Köttgen, A., Glazer, N. L., Dehghan, A., et al. (2009) · Nature Genetics · doi:10.1038/ng.466 · Cited by 356 · see citing works
Nelson, J. E., Wilson, L., Brunt, E. M., Yeh, M. M., Kleiner, D. E., Ünalp–Arida, A., & Kowdley, K. V. (2010) · Hepatology · doi:10.1002/hep.24038 · Cited by 354 · see citing works
“AST (U/L) 45 (32-68) 40 (31-56) 58 (39-77) 45 (33-63) 0.”
Iron at the interface of immunity and infection
Nairz, M., Haschka, D., Demetz, E., & Weiss, G. (2014) · Frontiers in Pharmacology · doi:10.3389/fphar.2014.00152 · Cited by 325 · see citing works
“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).”
BackgroundUnfolded Protein Response Signaling and Metabolic Diseases
Lee, J., & Özcan, U. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.r113.534743 · Cited by 306 · see citing works
“However, unlike ATF6, CREBH has shown to activate different sets of hepatic genes in the acute phase response (59), iron metabolism (60), gluconeogenesis (61), and TG metabolism (58).”
BackgroundHepcidin in Human Iron Disorders: Diagnostic Implications
Kroot, J. J., Tjalsma, H., Fleming, R. E., & Swinkels, D. W. (2011) · Clinical Chemistry · doi:10.1373/clinchem.2009.140053 · Cited by 246 · see citing works
Bacteria, the endoplasmic reticulum and the unfolded protein response: friends or foes?
Celli, J., & Tsolis, R. M. (2014) · Nature Reviews Microbiology · doi:10.1038/nrmicro3393 · Cited by 238 · see citing works
Molecular Mechanisms of Hepcidin Regulation: Implications for the Anemia of CKD
Babitt, J. L., & Lin, H. Y.-F. (2010) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2009.12.030 · Cited by 236 · see citing works
“ER stress also increases epcidin expression through CREBH binding and ransactivation of the hepcidin promoter (Fig 3).(80) R stress also has been suggested to transcriptionlly regulate hepcidin expression through CCAAT/ nhancer-binding protein (C/EBP) homologous proein (CHOP) and C/EBP , although this has not een link…”
BackgroundThe Spectrum of Achalasia: Lessons From Studies of Pathophysiology and High-Resolution Manometry
Kahrilas, P. J., & Boeckxstaens, G. E. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.08.038 · Cited by 234 · see citing works
Dongiovanni, P., Anstee, Q. M., & Valenti, L. V. C. (2013) · Current Pharmaceutical Design · doi:10.2174/13816128113199990381 · Cited by 231 · see citing works
“In Italian patients with NAFLD, the presence of the PiS and PiZ alleles was associated with hyperferritinemia and non-parenchymal iron accumulation, likely in response to the activation of the unfolded protein response in the endoplasmic reticulum [182], but on the other hand were not associated with more severe liver…”
BackgroundUeda, N., & Takasawa, K. (2018) · Nutrients · doi:10.3390/nu10091173 · Cited by 234 · see citing works
“Endoplasmic reticulum (ER) stress associated with inflammation increases hepcidin by activating SMAD1/5/8 [33], IL-6-dependent phosphorylated STAT3 [34] and ER stress-activated transcription factor, cyclic AMP response element–binding protein H (CREBH), which bind and activate hepcidin promoter activity [35].”
BackgroundHepcidin: regulation of the master iron regulator
Rishi, G., Wallace, D. F., & Subramaniam, V. N. (2015) · Bioscience Reports · doi:10.1042/bsr20150014 · Cited by 223 · see citing works
Fraenkel, P. G. (2016) · Medical Clinics of North America · doi:10.1016/j.mcna.2016.09.005 · Cited by 223 · see citing works
“Hepatocyte damage, via endoplasmic reticulum stress or oxidation, enhances C/EBPα [34, 35] or Stat3 activity [36], respectively, leading to increased Hepcidin expression.”
BackgroundFluorescent Diagnostic Probes in Neurodegenerative Diseases
Zhou, J., Jangili, P., Son, S., Ji, M. S., Won, M., & Kim, J. S. (2020) · Advanced Materials · doi:10.1002/adma.202001945 · Cited by 206 · see citing works
Asada, R., Kanemoto, S., Kondo, S., Saito, A., & Imaizumi, K. (2011) · The Journal of Biochemistry · doi:10.1093/jb/mvr041 · Cited by 197 · see citing works
Corradini, E., Meynard, D., Wu, Q., Chen, S., Ventura, P., Pietrangelo, A., & Babitt, J. L. (2011) · Hepatology · doi:10.1002/hep.24359 · Cited by 194 · see citing works
Self-citationThe Unfolded Protein Response in Secretory Cell Function
Moore, K. A., & Hollien, J. (2012) · Annual Review of Genetics · doi:10.1146/annurev-genet-110711-155644 · Cited by 178 · see citing works
Regulation of Iron Metabolism by Hepcidin under Conditions of Inflammation
Schmidt, P. J. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.r115.650150 · Cited by 181 · see citing works
“Importantly, hepcidin expression can be modulated by the transcription factors CHOP (CCAAT-enhancer-binding protein homologous protein), C/EBP (CCAAT-enhancer-binding protein ), and CREBH, which bind to specific binding sites on the hepcidin promoter (92, 93).”
BackgroundPietrangelo, A. (2016) · Liver International · doi:10.1111/liv.13020 · Cited by 174 · see citing works
“Endoplasmic reticulum (ER) stress involved in a number of pathophysiological states, including the inflammatory response, nutrient disorders and viral infection, can induce hepcidin through the cyclic adenosine monophosphate (cAMP) response element binding protein 3–like 3, CREB3L3 (also known as CREBH), and cause iro…”
BackgroundSelf-citationThe role of vitamin D in regulating the iron-hepcidin-ferroportin axis in monocytes
Zughaier, S. M., Alvarez, J. A., Sloan, J. H., Konrad, R. J., & Tangpricha, V. (2014) · Journal of Clinical & Translational Endocrinology · doi:10.1016/j.jcte.2014.01.003 · Cited by 174 · see citing works
“Further, endoplasmic reticulum (ER) stress is shown to dysregulate cellular iron homeostasis by inducing hepcidin expression [64].”
BackgroundPiperi, C., Adamopoulos, C., Dalagiorgou, G., Diamanti‐Kandarakis, E., & Papavassiliou, A. G. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-3408 · Cited by 167 · see citing works
“In hepatocytes, ER stress also induces the production of hepcidin, an iron-regulating peptide hormone, leading to abnormal iron metabolism (117).”
BackgroundCREB3 Transcription Factors: ER-Golgi Stress Transducers as Hubs for Cellular Homeostasis
Sampieri, L., Giusto, P. D., & Álvarez, C. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00123 · Cited by 164 · see citing works
“, 2006) and hepcidin-mediated iron metabolism (Vecchi et al., 2009).”
Angiogenesis and liver fibrosis
Elpek, G. Ö. (2015) · World Journal of Hepatology · doi:10.4254/wjh.v7.i3.377 · Cited by 157 · see citing works
Iron in the Tumor Microenvironment-Connecting the Dots
Pfeifhofer-Obermair, C., Tymoszuk, P., Petzer, V., Weiss, G., & Nairz, M. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00549 · Cited by 151 · see citing works
Ferroportin disease: pathogenesis, diagnosis and treatment
Pietrangelo, A. (2017) · Haematologica · doi:10.3324/haematol.2017.170720 · Cited by 151 · see citing works
“Hepcidin is produced by the liver in response to iron, inflammation, and a variety of stressors.(22-25) Hepcidin binds to the extracellular loop of FPN1 and triggers its ubiquitinylation on lysine residues located in the intracellular domain leading to internalization and degradation in lysosomes.”
BackgroundSelf-citationHypoxia induced downregulation of hepcidin is mediated by platelet derived growth factor BB
Sonnweber, T., Nachbaur, D., Schroll, A., Nairz, M., Seifert, M., Demetz, E., Haschka, D., Mitterstiller, A.-M., Kleinsasser, A., Burtscher, M., et al. (2014) · Gut · doi:10.1136/gutjnl-2013-305317 · Cited by 145 · see citing works
Self-citationIntestinal Ferritin H Is Required for an Accurate Control of Iron Absorption
Vanoaica, L., Darshan, D., Richman, L., Schümann, K., & Kühn, L. C. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.08.003 · Cited by 137 · see citing works
Mechanisms of Alcohol-Induced Endoplasmic Reticulum Stress and Organ Injuries
Ji, C. (2011) · Biochemistry Research International · doi:10.1155/2012/216450 · Cited by 137 · see citing works
Genetics, genetic testing, and management of hemochromatosis: 15 years since hepcidin
Pietrangelo, A. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.06.045 · Cited by 136 · see citing works
Self-citationFerroportin disease: a systematic meta-analysis of clinical and molecular findings
Mayr, R., Janecke, A. R., Schranz, M., Griffiths, W. J. H., Vogel, W., Pietrangelo, A., & Zoller, H. (2010) · Journal of Hepatology · doi:10.1016/j.jhep.2010.05.016 · Cited by 133 · see citing works
“Hepcidin is secreted by hepatocytes into the circulation in response to pro-inflammatory cytokines, hepatocellular iron loading, and endoplasmic reticulum stress [21,22].”
BackgroundSelf-citationGluconeogenic Signals Regulate Iron Homeostasis via Hepcidin in Mice
Vecchi, C., Montosi, G., Garuti, C., Corradini, E., Sabelli, M., Canali, S., & Pietrangelo, A. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.12.016 · Cited by 123 · see citing works
Self-citationIron Regulatory Proteins: From Molecular Mechanisms to Drug Development
Recalcati, S., Minotti, G., & Cairo, G. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.2983 · Cited by 123 · see citing works
“…of this article at www .liebertonline.com = ars). expression is downregulated in response to iron deficiency (142) anemia or hypoxia (152) (which increases iron release and availability), and upregulated in response to iron over-load, inflammation (142), or endoplasmic reticulum stress (149, 210).”
Anemia of chronic disorders: new diagnostic tools and new treatment strategies
Weiss, G. (2015) · Seminars in Hematology · doi:10.1053/j.seminhematol.2015.07.004 · Cited by 116 · see citing works
Hepcidin in human iron disorders: Therapeutic implications
Pietrangelo, A. (2010) · Journal of Hepatology · doi:10.1016/j.jhep.2010.08.004 · Cited by 115 · see citing works
“CREBH has been recently implicated in the transcriptional activation of hepcidin during ER stress and also seems to partially contribute to hepcidin response to inflammatory stimuli in vivo [18].”
Self-citationThe Unfolded Protein Response in Fatty Liver Disease
Green, R. R., & Henkel, A. S. (2013) · Seminars in Liver Disease · doi:10.1055/s-0033-1358522 · Cited by 108 · see citing works
Iron homeostasis and disorders revisited in the sepsis
Liu, Q., Wu, J., Zhang, X., Wu, X., Zhao, Y., & Ren, J. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.01.025 · Cited by 112 · see citing works
Hemojuvelin and bone morphogenetic protein (BMP) signaling in iron homeostasis
Core, A. B., Canali, S., & Babitt, J. L. (2014) · Frontiers in Pharmacology · doi:10.3389/fphar.2014.00104 · Cited by 107 · see citing works
“…growth factor (EGF), endoplasmic reticulum stress, gluconeogenic signals and the Ras/RAF and mTOR signaling pathways (Oliveira et al., 2009; Vecchi et al., 2009, 2014; Goodnough et al., 2012; Hou et al., 2012; Yang et al., 2012; Guo et al., 2013; Latour et al., 2014; Mleczko-Sanecka et…”
BackgroundCorradini, E., Rozier, M., Meynard, D., Odhiambo, A., Lin, H. Y.-F., Feng, Q., Migas, M. C., Britton, R. S., Babitt, J. L., & Fleming, R. E. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.06.077 · Cited by 102 · see citing works
Hepcidin Signaling in Health and Disease: Ironing Out the Details
Kowdley, K. V., Gochanour, E. M., Sundaram, V., Shah, R. A., & Handa, P. (2021) · Hepatology Communications · doi:10.1002/hep4.1717 · Cited by 105 · see citing works
The iron-regulatory hormone hepcidin: A possible therapeutic target?
Rochette, L., Gudjoncik, A., Guénancia, C., Zeller, M., Cottin, Y., & Vergely, C. (2014) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2014.09.004 · Cited by 99 · see citing works
Quercetin and iron metabolism: What we know and what we need to know
Xiao, L., Luo, G., Tang, Y., & Yao, P. (2018) · Food and Chemical Toxicology · doi:10.1016/j.fct.2018.02.022 · Cited by 101 · see citing works
Endoplasmic Reticulum Stress and the Unfolded Protein Response in Nonalcoholic Fatty Liver Disease
Gentile, C. L., Frye, M. A., & Pagliassotti, M. J. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3790 · Cited by 99 · see citing works
“have demonstrated that the UPR can regulate hepatic iron metabolism (110, 168).”
BackgroundCurcumin a potent cancer preventive agent: Mechanisms of cancer cell killing
Tuorkey, M. J. (2014) · Interventional Medicine and Applied Science · doi:10.1556/imas.6.2014.4.1 · Cited by 98 · see citing works
“Gadd153, growth arrest and DNA damage-inducible protein, is activated by endoplasmic reticulum (ER) stress, resulting in the induction of oxidative stress, generation of reactive oxygen species (ROS), and disturbing iron homeostasis, which in turn mediates cellular-damage/ apoptosis [41, 42].”
BackgroundIron Metabolism and Brain Development in Premature Infants
Wang, Y., Wu, Y., Li, T., Wang, X., & Zhu, C. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00463 · Cited by 98 · see citing works
Role of Serum Uric Acid and Ferritin in the Development and Progression of NAFLD
Lombardi, R., Pisano, G., & Fargion, S. R. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17040548 · Cited by 97 · see citing works
Bhattacharya, A., Sun, S., Wang, H., Liu, M. R., Long, Q., Yin, L., Kersten, S., Zhang, K., & Qi, L. (2018) · The EMBO Journal · doi:10.15252/embj.201899277 · Cited by 88 · see citing works
“Unlike Ppar a , Crebh encodes an ER membrane-anchored transcription factor, which requires regulated intramem-brane proteolysis at the Golgi to generate the Crebh N-terminal fragment (Crebh-N) (Vecchi et al , 2009; Zhang et al , 2012a,b; Zhang et al , 2006).”
Self-citationXu, Y., Alfaro-Magallanes, V. M., & Babitt, J. L. (2020) · British Journal of Haematology · doi:10.1111/bjh.17252 · Cited by 94 · see citing works
“Protein misfolding-induced endoplasmic reticulum stress serves as an intracellular signal to transcriptionally activate hepcidin via cyclic AMP response element-binding protein H (CREBH) and the SMAD signalling pathway.(87,88) Post-transcriptional hepcidin regulation by the RNA-binding protein Hu antigen R (HuR) may a…”
BackgroundLane, D. J. R., Mills, T. M., Shafie, N. H., Merlot, A. M., Moussa, R., Kalinowski, D. S., Kovačević, Ž., & Richardson, D. R. (2014) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2014.01.005 · Cited by 87 · see citing works
Hepatic ZIP14-mediated zinc transport is required for adaptation to endoplasmic reticulum stress
Kim, M., Aydemir, T. B., Kim, J.-H., & Cousins, R. J. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1704012114 · Cited by 87 · see citing works
“TM have been shown to exhibit hypoferremia and iron sequestration in the spleen and liver (36).”
BackgroundBone morphogenic proteins in iron homeostasis
Xiao, X., Alfaro-Magallanes, V. M., & Babitt, J. L. (2020) · Bone · doi:10.1016/j.bone.2020.115495 · Cited by 88 · see citing works
“Endoplasmic reticulum (ER) stress has also been shown to increase hepcidin expression both in vitro and in vivo [124].”
BackgroundStress Signal Network between Hypoxia and ER Stress in Chronic Kidney Disease
Maekawa, H., & Inagi, R. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00074 · Cited by 83 · see citing works
“Hepcidin induction in response to exogenously administered toxins or the accumulation of unfolded proteins in the ER is defective in CREBH knockout mice, indicating a role for CREBH in ER stress–regulated hepcidin expression (Vecchi et al., 2009).”
BackgroundHino, K., Saito, A., Kido, M., Kanemoto, S., Asada, R., Takai, T., Cui, M., Cui, X., & Imaizumi, K. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.543322 · Cited by 84 · see citing works
Understanding anemia of chronic disease
Fraenkel, P. G. (2015) · Hematology · doi:10.1182/asheducation-2015.1.14 · Cited by 83 · see citing works
Endoplasmic Reticulum Stress and Ethanol Neurotoxicity
Yang, F., & Luo, J. (2015) · Biomolecules · doi:10.3390/biom5042538 · Cited by 82 · see citing works
“Since ER stress can affect the expression of hepcidin [91], a key regulator of iron homeostasis [92], a positive feedback may further enhance the effect of ethanol, inducing ER overload and mitochondrial dysfunction.”
Peleman, C., Francque, S., & Berghe, T. V. (2024) · EBioMedicine · doi:10.1016/j.ebiom.2024.105088 · Cited by 86 · see citing works
“153,154 MASLD patients with macrophage iron accumulation displayed higher MASLD activity score and more TUNEL positive foci in their livers compared to the parenchymal pattern or no iron overload.”
BackgroundArensdorf, A. M., Diedrichs, D. R., & Rutkowski, D. T. (2013) · Frontiers in Genetics · doi:10.3389/fgene.2013.00256 · Cited by 81 · see citing works
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 82 · see citing works
Prasanthi, J. R. P., Larson, T., Schommer, J., & Ghribi, O. (2011) · PLoS ONE · doi:10.1371/journal.pone.0026420 · Cited by 80 · see citing works
“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 78 · see citing works
Kushner, I., Samols, D. R., & Magrey, M. (2010) · Arthritis Care & Research · doi:10.1002/acr.20052 · Cited by 78 · see citing works
“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 76 · see citing works
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 76 · see citing works
“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 75 · see citing works
“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 · see citing works
“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 · see citing works
“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 71 · see citing works
“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 72 · see citing works
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 · see citing works
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 67 · see citing works
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 65 · see citing works
“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 · see citing works
Chan, C., Kok, K., & Jin, D. (2011) · Cell & Bioscience · doi:10.1186/2045-3701-1-6 · Cited by 64 · see citing works
“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 61 · see citing works
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 · see citing works
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 63 · see citing works
“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 62 · see citing works
Vela, D. (2018) · Molecular Medicine · doi:10.1186/s10020-018-0008-7 · Cited by 63 · see citing works
“(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 62 · see citing works
“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 · see citing works
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 · see citing works
“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 61 · see citing works
“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 · see citing works
“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 · see citing works
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
