Alcohol metabolism-mediated oxidative stress down-regulates hepcidin transcription and leads to increased duodenal iron transporter expression.
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 alpha (C/EBPalpha) but not beta. Interestingly, the antioxidants vitamin E and N-acetylcysteine abolished both the alcohol-mediated down-regulation of C/EBPalpha 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/EBPalpha, which in turn leads to increased duodenal iron transport.
Harrison-Findik
Duygu Dee
DD
Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198-5820, USA. dharrisonfindik@unmc.edu
Schafer
Denise
D
Klein
Elizabeth
E
Timchenko
Nikolai A
NA
Kulaksiz
Hasan
H
Clemens
Dahn
D
Fein
Evelyn
E
Andriopoulos
Billy
B
Pantopoulos
Kostas
K
Gollan
John
J
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis* / Q000235:genetics; D000975:Antioxidants / Q000378:metabolism; D001692:Biological Transport; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D004386:Duodenum / Q000378:metabolism*; D000431:Ethanol / Q000378:metabolism*; D005260:Female; D000077604:Fomepizole; D005786:Gene Expression Regulation; D064451:Hepcidins; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008297:Male; D051379:Mice; D018384:Oxidative Stress; D011720:Pyrazoles / Q000494:pharmacology; D017382:Reactive Oxygen Species
D023181:Antimicrobial Cationic Peptides; D000975:Antioxidants; D022763:CCAAT-Enhancer-Binding Protein-alpha; D022782:CCAAT-Enhancer-Binding Protein-beta; C578702:HAMP protein, human; C579599:Hamp protein, mouse; D064451:Hepcidins; D011720:Pyrazoles; D017382:Reactive Oxygen Species; D000431:Ethanol; D000077604:Fomepizole; D007501:Iron