The Interaction of Alcohol and Iron-Overload in the in-vivo Regulation of Iron Responsive Genes

Patients with alcoholic liver disease (ALD) frequently exhibit iron overload but the molecular mechanisms of alcohol and iron interaction are still unclear. This study investigated the role of alcohol in the regulation of ironresponsive genes, hepcidin, hemojuvelin and leap-2 in both dietary and genetic mouse models. Ethanol significantly down-regulated liver hepcidin and hemojuvelin gene expression. However, leap-2 gene expression was increased in mice treated with 10 % and 20 % ethanol. We further studied the combined effect of alcohol and iron on the regulation of iron metabolism. Iron overload up-regulated the expression of hepcidin, hemojuvelin and leap-2 genes. Interestingly, ethanol reversed the effect of iron on hepcidin and leap-2 gene expression. This effect of ethanol was evident in both dietary and genetic iron overload models. However, further treatment with ethanol did not alter the effect of iron on leap-2 gene expression. Moreover, ethanol and iron together resulted in fatty liver, which was exacerbated with an increasing ethanol concentration. However, mice treated with alcohol or iron alone did not exhibit lipid vesicles in the liver. Collectively, these results suggest that alcohol alters the regulation of iron-responsive genes leading to abnormal iron homeostasis, which may play a role in the progression of alcoholic liver disease.