Hepatitis C and alcohol exacerbate liver injury by suppression of FOXO3.
Hepatitis C virus (HCV) infection exacerbates alcoholic liver injury by mechanisms that include enhanced oxidative stress. The forkhead box transcription factor FOXO3 is an important component of the antioxidant stress response that can be altered by HCV. To test whether FOXO3 is protective for alcoholic liver injury, we 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.
Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.
Batbayar
B
Tumurbaatar
Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.
Irina
I
Tikhanovich
Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.
Zhuan
Z
Li
Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.
Jinyu
J
Ren
Department of Pharmacology and Toxicology, University of Kansas Medical Center, Kansas City, Kansas.
Robert
R
Ralston
Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.
Sudhakiranmayi
S
Kuravi
Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.
Roosevelt
R
Campbell
Department of Physiology, University of Kansas Medical Center, Kansas City, Kansas.
Gaurav
G
Chaturvedi
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California; Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, Palo Alto, California.
Ting-Ting
TT
Huang
Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.
Jie
J
Zhao
Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas.
Junfang
J
Hao
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas.
Maura
M
O'Neil
Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas. Electronic address: sweinman@kumc.edu.
Steven A
SA
Weinman
D000818:Animals; D002492:Central Nervous System Depressants / Q000009:adverse effects* / Q000494:pharmacology; D000431:Ethanol / Q000009:adverse effects* / Q000494:pharmacology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism*; D006526:Hepatitis C / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008108:Liver Diseases, Alcoholic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D000099156:Superoxide Dismutase 2
D002492:Central Nervous System Depressants; D000431:Ethanol; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C474033:FoxO3 protein, mouse