Hepcidin Regulation in Wild-Type and Hfe Knockout Mice in Response to Alcohol Consumption: Evidence for an Alcohol-Induced Hypoxic Response

Background /Aims: Expression of Hamp1, the gene encoding the iron regulatory peptide hepcidin, is inappropriately low in HFE‐associated hereditary hemochromatosis and Hfe knockout mice (Hfe−/−). Since chronic alcohol consumption is also associated with disturbances in iron metabolism, we investigated the effects of alcohol consumption on hepcidin mRNA expression in Hfe−/− mice. Methods: Hfe −/− and C57BL/6 (wild‐type) mice were pair‐fed either an alcohol liquid diet or control diet for up to 8 weeks. The mRNA levels of hepcidin and ferroportin were measured at the mRNA level by RT‐PCR and protein expression of hypoxia inducible factor‐1 alpha (HIF‐1α) was measured by western blot. Results: Hamp1 mRNA expression was significantly decreased and duodenal ferroportin expression was increased in alcohol‐fed wild‐type mice at 8 weeks. Time course experiments showed that the decrease in hepcidin mRNA was not immediate, but was significant by 4 weeks. Consistent with the genetic defect, Hamp1 mRNA was decreased and duodenal ferroportin mRNA expression was increased in Hfe−/− mice fed on the control diet compared with wild‐type animals and alcohol further exacerbated these effects. HIF‐1α protein levels were elevated in alcohol‐fed wild‐type animals compared with controls. Conclusion: Alcohol may decrease Hamp1 gene expression independently of the HFE pathway possibly via alcohol‐induced hypoxia.