Hepcidin Regulation in Wild-Type and Hfe Knockout Mice in Response to Alcohol Consumption: Evidence for an Alcohol-Induced Hypoxic Response
Article first published online: 4 MAY 2009
Copyright © 2009 by the Research Society on Alcoholism
Alcoholism: Clinical and Experimental Research
Volume 33, Issue 8, pages 1391–1400, August 2009
How to Cite
Heritage, M. L., Murphy, T. L., Bridle, K. R., Anderson, G. J., Crawford, D. H. G. and Fletcher, L. M. (2009), Hepcidin Regulation in Wild-Type and Hfe Knockout Mice in Response to Alcohol Consumption: Evidence for an Alcohol-Induced Hypoxic Response. Alcoholism: Clinical and Experimental Research, 33: 1391–1400. doi: 10.1111/j.1530-0277.2009.00969.x
- Issue published online: 27 JUL 2009
- Article first published online: 4 MAY 2009
- Received for publication May 12, 2008; accepted March 14, 2008.
- Iron Regulation;
- Liver Disease;
- CEBP α;
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.