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

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

Research output: Contribution to journalArticle

203 Scopus citations

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Harrison-Findik, D. D., Schafer, D., Klein, E., Timchenko, N. A., Kulaksiz, H., Clemens, D., 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, 281(32), 22974-22982. https://doi.org/10.1074/jbc.M602098200