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Hepcidin Regulation in Wild‐Type and Hfe Knockout Mice in Response to Alcohol Consumption: Evidence for an Alcohol‐Induced Hypoxic Response
Author(s) -
Heritage Mandy L.,
Murphy Therese L.,
Bridle Kim R.,
Anderson Gregory J.,
Crawford Darrell H. G.,
Fletcher Linda M.
Publication year - 2009
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.2009.00969.x
Subject(s) - hepcidin , endocrinology , medicine , hemochromatosis , ferroportin , hereditary hemochromatosis , knockout mouse , wild type , messenger rna , alcohol , gene expression , hypoxia (environmental) , western blot , biology , chemistry , gene , receptor , biochemistry , inflammation , oxygen , organic chemistry , mutant
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.