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Transcription factor may protect against hepatic injury caused by hepatitis C and alcohol
Date:11/10/2013

greater concentration of FOXO3 in the cytosol of the cell compared to the nuclear location found in other types of mice.

Weinman continues, "One of the important unanswered questions about alcoholic liver disease has been why only a minority of those who drink, including those who drink heavily, ever develop liver disease. In most people, the liver has efficient protection mechanisms against alcohol. Our results indicate that FOXO3 is a novel alcohol protection factor that is disrupted by the HCV-alcohol combination. We therefore think that modulation of the FOXO3 pathway is a potential therapeutic approach for HCV-alcohol-induced liver injury."

In cell culture, either HCV or alcohol alone produced an increase in FOXO3 transcriptional activity. However, Weinman and colleagues found that although the effects of both of these stress stimuli on FOXO3 were similar, the mechanisms of action were different. For example, although HCV activation was associated with translocation of FOXO3 from cytosol to the nucleus, alcohol produced transcriptional activation without a prominent change in the nuclear-cytosolic ratio. Another difference found was that HCV, but not alcohol, caused a miRNA-dependent suppression of SOD2 translation.

That HCV infection and alcohol exposure appear to work in synergy to produce effects that are different from those seen with either alone was a "novel and unexpected" finding, says Weinman. The suppression of FOXO3 by the combination of HCV and alcohol is attributed in part to nuclear export and a decreased protein half-life that does not occur with either HCV or alcohol alone. "The results indicate that FOXO3 is a novel alcohol protection factor that is disrupted by the HCV-alcohol combination," concludes Weinman.

In the same issue of The American Journal of Pathology, another team of investigators from the University of Kansas Medical Center, led by Dr. Wen-Xing Ding, PhD, Department of Pharmacology, Tox
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Contact: Eileen Leahy
ajpmedia@elsevier.com
732-238-3628
Elsevier Health Sciences
Source:Eurekalert

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