Supported by grants from The National Health and Medical Research Council of Australia and The Australian Brewers' Medical Research Foundation. KB is a recipient of a Gastroenterological Society of Australia Postdoctoral Fellowship.
Hepcidin Is Down-regulated in Alcoholic Liver Injury: Implications for the Pathogenesis of Alcoholic Liver Disease
Article first published online: 6 JAN 2006
Alcoholism: Clinical and Experimental Research
Volume 30, Issue 1, pages 106–112, January 2006
How to Cite
Bridle, K., Cheung, T.-K., Murphy, T., Walters, M., Anderson, G., Crawford, D. G. and Fletcher, L. M. (2006), Hepcidin Is Down-regulated in Alcoholic Liver Injury: Implications for the Pathogenesis of Alcoholic Liver Disease. Alcoholism: Clinical and Experimental Research, 30: 106–112. doi: 10.1111/j.1530-0277.2006.00002.x
- Issue published online: 6 JAN 2006
- Article first published online: 6 JAN 2006
- Received for publication April 22, 2005; accepted September 23, 2005.
Background: Alcoholic liver disease is known to be associated with abnormal iron homeostasis, and iron metabolism itself is regulated by the liver-derived peptide hepcidin. Both CCAAT enhancer binding protein alpha (C/EBPα) and interleukin 6 (IL-6) have been shown to regulate hepcidin gene transcription.
Aim: To investigate mechanisms underlying alcohol-induced disturbances in iron homeostasis by measuring the expression of hepcidin and C/EBPα mRNA using in vivo and in vitro models of alcoholic liver injury.
Methods: Male rats were pair-fed an alcoholic liquid diet for 12 weeks. RT-PCR was performed on liver tissue using specific primers for hepcidin and C/EBPα. The effect of alcohol on hepcidin and C/EBPα gene expression was also determined in isolated hepatocytes, HuH-7 cells and HepG2 cells treated with 50 mM ethanol, 200 μM acetaldehyde, and/or 20 ng/ml IL-6.
Results: Hepcidin and C/EBPα mRNA expression were significantly decreased in alcohol-fed rats compared with pair-fed controls (6-fold p<0.001 and 2.2-fold p<0.0002 reduction, respectively) and hepatic lipid peroxidation was increased by 32.5% (p<0.05) in alcohol-fed rats compared with controls. Hepcidin gene expression was not altered significantly in cells cultured in the presence of 50 mM ethanol. Following 24 hour stimulation by IL-6, there was a 4-fold increase in hepcidin expression in hepatocytes and a 9-fold increase in HuH-7 cells. Ethanol (50 mM) attenuated the IL-6-induced increase in hepcidin expression in HuH-7 cells (9-fold to a 4-fold increase) but not in hepatocytes. Acetaldehyde had no effect on hepcidin gene expression in cells in culture.
Conclusion: The down-regulation of hepcidin and C/EBPα gene expression shown in vivo implies disturbed iron sensing contributing to the hepatosiderosis seen in alcoholic liver disease, possibly by mechanisms involving the IL-6 signaling cascade.