Alcohol reduces and iron increases liver hepcidin synthesis. This study investigates the interaction of alcohol and iron in the regulation of hepcidin messenger RNA (mRNA) expression in animal models. Mice were administered 10% ethanol for 7 days after an iron-overloaded diet. Rats were administered regular or ethanol-Lieber De Carli diets for 7 weeks with or without carbonyl iron. Hfe ؊/؊ mice were used as a model for genetic iron overload. Hepcidin mRNA expression was determined by real-time polymerase chain reaction (PCR) and northern blotting. Iron elevated and alcohol decreased liver hepcidin expression in mice and rats. Interestingly, despite iron overload, alcohol was capable of suppressing the up-regulation of hepcidin mRNA expression in both models. Liver iron and ferritin protein expression was elevated in alcohol-treated rats, but was not elevated further in rats treated with both iron and alcohol. Duodenal ferroportin protein expression was increased both in alcohol-treated mice and in mice treated with alcohol and iron. Hfe ؊/؊ mice treated with ethanol for 7 days exhibited a further decrease in hepcidin mRNA expression. The iron-induced increase in DNA-binding activity of the transcription factor CCAAT/ enhancer binding protein alpha (C/EBP alpha) was also suppressed by alcohol. Conclusion: Alcohol abolishes the iron-induced up-regulation of both liver hepcidin transcription and the DNA-binding activity of C/EBP alpha. Of note, hepcidin protects the body from the harmful effects of iron overload. Our findings therefore suggest that alcohol negates the protective effect of hepcidin, which may have implications for the liver injury observed in alcoholic liver disease and genetic hemochromatosis in combination with alcohol. (HEPATOLOGY 2007;46:1979-1985 H epcidin is a circulatory peptide that is synthesized in the liver and acts as the key regulator of iron metabolism by modulating iron absorption through the duodenum and the release of iron from macrophages. 1,2 We have recently demonstrated that acute alcohol-induced oxidative stress down-regulates liver hepcidin transcripts in mice by altering the DNA-binding activity of the transcription factor CCAAT/enhancer binding protein (C/EBP) alpha. 3 Alcohol-mediated down-regulation of liver hepcidin mRNA expression occurred without associated changes in liver histology or triglycerides. 3 Mice exposed to ethanol for 7 days exhibited elevated iron transporter protein expression in the duodenum. This was abolished by injecting mice with hepcidin peptide. 3 Bridle et al. also have reported reduced hepcidin mRNA expression in rats with chronic alcohol exposure. 4 These results demonstrated a role for alcohol in the regulation of iron metabolism by regulating the expression of hepcidin in the liver.Liver hepcidin messenger RNA (mRNA) expression is regulated inversely by iron and alcohol. 2-4 Namely, iron up-regulates, whereas alcohol down-regulates, liver hepcidin expression. However, the combined effect of alcohol and iron in the regulation of hepcidin expres...
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