The working hypothesis to explain the progression from mild (fatty liver) to more severe forms of alcoholic liver disease (e.g., fibrosis, cirrhosis, alcoholic hepatitis and hepatocellular carcinoma) has been that alcohol requires a secondary initiator or trigger for this progression, or that alcohol is secondary to some other initiating event.  Hepatitis C virus (HCV) infection has been a strong candidate for this role. A recent study provides mechanistic details for this pathway and identifies FOXO3 (forkhead box transcription factor) as potential target for therapeutic intervention in alcoholic liver disease.

To test whether FOXO3 is protective for alcoholic liver injury, researchers fed alcohol to FOXO3(-/-) mice. After 3 weeks, one third of these mice developed severe hepatic steatosis, neutrophilic infiltration, and >10-fold alanine aminotransferase (ALT) elevations. In cell culture, either alcohol or HCV infection alone increased FOXO3 transcriptional activity and expression of target genes, but the combination of HCV and alcohol together caused loss of nuclear FOXO3 and decreased its transcriptional activity.

This was accompanied by increased phosphorylation of FOXO3. Mice expressing HCV structural proteins on a background of reduced expression of superoxide dismutase 2 (SOD2; Sod2(+/-)) also had increased liver sensitivity to alcohol, with elevated ALT, steatosis, and lobular inflammation. Elevated ALT was associated with an alcohol-induced decrease in SOD2 and redistribution of FOXO3 to the cytosol.

These results demonstrate that FOXO3 functions as a protective factor preventing alcoholic liver injury. The combination of HCV and alcohol, but not either condition alone, inactivates FOXO3, causing a decrease in expression of its target genes and an increase in liver injury. Modulation of the FOXO3 pathway is a potential therapeutic approach for HCV-alcohol-induced liver injury.