Alcohol metabolism-mediated oxidative stress down-regulates hepcidin transcription and leads to increased duodenal iron transporter expression

Duygu Dee Harrison-Findik, Daniel Francis Schafer, Elizabeth Klein, Nikolai A. Timchenko, Hasan Kulaksiz, Dahn L Clemens, Evelyn Fein, Billy Andriopoulos, Kostas Pantopoulos, John Gollan

Research output: Contribution to journalArticle

198 Citations (Scopus)

Abstract

Patients with alcoholic liver disease frequently exhibit iron overload in association with increased hepatic fibrosis. Even moderate alcohol consumption elevates body iron stores; however, the underlying molecular mechanisms are unknown. Hepcidin, a circulatory peptide synthesized in the liver, is a key mediator of iron metabolism. Ethanol metabolism significantly down-regulated both in vitro and in vivo hepcidin mRNA and protein expression. 4-Methylpyrazole, a specific inhibitor of the alcohol-metabolizing enzymes, abolished the effects of ethanol on hepcidin. However, ethanol did not alter the expression of transferrin receptor1 and ferritin or the activation of iron regulatory RNA-binding proteins, IRP1 and IRP2. Mice maintained on 10-20% ethanol for 7 days displayed down-regulation of liver hepcidin expression without changes in liver triglycerides or histology. This was accompanied by elevated duodenal divalent metal transporter1 and ferroportin protein expression. Injection of hepcidin peptide negated the effect of ethanol on duodenal iron transporters. Ethanol down-regulated hepcidin promoter activity and the DNA binding activity of CCAAT/enhancer-binding protein α (C/EBPα) but not β. Interestingly, the antioxidants vitamin E and N-acetylcysteine abolished both the alcohol-mediated down-regulation of C/EBPα binding activity and hepcidin expression in the liver and the up-regulation of duodenal divalent metal transporter 1. Collectively, these findings indicate that alcohol metabolism-mediated oxidative stress regulates hepcidin transcription via C/EBPα, which in turn leads to increased duodenal iron transport.

Original languageEnglish (US)
Pages (from-to)22974-22982
Number of pages9
JournalJournal of Biological Chemistry
Volume281
Issue number32
DOIs
StatePublished - Aug 11 2006

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Hepcidins
Oxidative stress
Transcription
Metabolism
Oxidative Stress
Down-Regulation
Iron
Alcohols
Ethanol
Liver
CCAAT-Enhancer-Binding Proteins
Iron-Regulatory Proteins
Alcoholic Liver Diseases
Peptides
Histology
Iron Overload
RNA-Binding Proteins
Acetylcysteine
Transferrin
Ferritins

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Alcohol metabolism-mediated oxidative stress down-regulates hepcidin transcription and leads to increased duodenal iron transporter expression. / Harrison-Findik, Duygu Dee; Schafer, Daniel Francis; Klein, Elizabeth; Timchenko, Nikolai A.; Kulaksiz, Hasan; Clemens, Dahn L; Fein, Evelyn; Andriopoulos, Billy; Pantopoulos, Kostas; Gollan, John.

In: Journal of Biological Chemistry, Vol. 281, No. 32, 11.08.2006, p. 22974-22982.

Research output: Contribution to journalArticle

Harrison-Findik, DD, Schafer, DF, Klein, E, Timchenko, NA, Kulaksiz, H, Clemens, DL, Fein, E, Andriopoulos, B, Pantopoulos, K & Gollan, J 2006, 'Alcohol metabolism-mediated oxidative stress down-regulates hepcidin transcription and leads to increased duodenal iron transporter expression', Journal of Biological Chemistry, vol. 281, no. 32, pp. 22974-22982. https://doi.org/10.1074/jbc.M602098200
Harrison-Findik, Duygu Dee ; Schafer, Daniel Francis ; Klein, Elizabeth ; Timchenko, Nikolai A. ; Kulaksiz, Hasan ; Clemens, Dahn L ; Fein, Evelyn ; Andriopoulos, Billy ; Pantopoulos, Kostas ; Gollan, John. / Alcohol metabolism-mediated oxidative stress down-regulates hepcidin transcription and leads to increased duodenal iron transporter expression. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 32. pp. 22974-22982.
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AU - Kulaksiz, Hasan

AU - Clemens, Dahn L

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AB - Patients with alcoholic liver disease frequently exhibit iron overload in association with increased hepatic fibrosis. Even moderate alcohol consumption elevates body iron stores; however, the underlying molecular mechanisms are unknown. Hepcidin, a circulatory peptide synthesized in the liver, is a key mediator of iron metabolism. Ethanol metabolism significantly down-regulated both in vitro and in vivo hepcidin mRNA and protein expression. 4-Methylpyrazole, a specific inhibitor of the alcohol-metabolizing enzymes, abolished the effects of ethanol on hepcidin. However, ethanol did not alter the expression of transferrin receptor1 and ferritin or the activation of iron regulatory RNA-binding proteins, IRP1 and IRP2. Mice maintained on 10-20% ethanol for 7 days displayed down-regulation of liver hepcidin expression without changes in liver triglycerides or histology. This was accompanied by elevated duodenal divalent metal transporter1 and ferroportin protein expression. Injection of hepcidin peptide negated the effect of ethanol on duodenal iron transporters. Ethanol down-regulated hepcidin promoter activity and the DNA binding activity of CCAAT/enhancer-binding protein α (C/EBPα) but not β. Interestingly, the antioxidants vitamin E and N-acetylcysteine abolished both the alcohol-mediated down-regulation of C/EBPα binding activity and hepcidin expression in the liver and the up-regulation of duodenal divalent metal transporter 1. Collectively, these findings indicate that alcohol metabolism-mediated oxidative stress regulates hepcidin transcription via C/EBPα, which in turn leads to increased duodenal iron transport.

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