Alcohol and hepatitis C virus core protein additively increase lipid peroxidation and synergistically trigger hepatic cytokine expression in a transgenic mouse model.
OBJECTIVE
Alcohol consumption accelerates the appearance of liver fibrosis and hepatocellular carcinoma in patients with chronic hepatitis C virus (HCV) infection, but the mechanisms of these interactions are unknown. We therefore investigated the effects of chronic ethanol consumption in HCV core protein-expressing transgenic mice.


METHODS
Ethanol was progressively added (up to 20%) to the drinking water that was given ad libidum.


RESULTS
In vivo fatty acid oxidation was not inhibited by ethanol consumption and/or HCV core expression. Both chronic ethanol consumption and HCV core expression decreased hepatic lipoprotein secretion and caused steatosis, but had no additive effects on lipoprotein secretion or steatosis. However, chronic ethanol consumption and HCV core protein additively increased lipid peroxidation and acted synergistically to increase the hepatic expression of transforming growth factor-beta (TGF-beta) and, to a less extent, tumor necrosis factor-alpha (TNF-alpha).


CONCLUSIONS
HCV core protein expression and chronic alcohol consumption have no effects on in vivo fatty acid oxidation and do not additively impair hepatic lipoprotein secretion, but additively increase hepatic lipid peroxidation and synergistically increase hepatic TNF-alpha and TGF-beta expression. These effects may be involved in the activation of fibrogenesis and the development of hepatocellular carcinoma in patients cumulating alcohol abuse and HCV infection.
Perlemuter
Gabriel
G
Liver Cancer and Molecular Virology, Institut National de la Santé et de la Recherche Médicale Unité 370, Faculté de Médecine Necker-Enfants Malades, 156 rue de Vaugirard, 75730 Paris Cedex 15, France.
Lettéron
Philippe
P
Carnot
Françoise
F
Zavala
Flora
F
Pessayre
Dominique
D
Nalpas
Bertrand
B
Bréchot
Christian
C
D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology; D004195:Disease Models, Animal; D000431:Ethanol / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D016174:Hepacivirus / Q000235:genetics*; D006512:Hepatitis B Core Antigens / Q000235:genetics* / Q000378:metabolism; D015227:Lipid Peroxidation; D008074:Lipoproteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008108:Liver Diseases, Alcoholic / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016212:Transforming Growth Factor beta / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D002492:Central Nervous System Depressants; D005227:Fatty Acids; D006512:Hepatitis B Core Antigens; D008074:Lipoproteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol