Carcinogenesis, Vol. 22, No. 8, 1213-1219,
August 2001
© 2001 Oxford University Press
CARCINOGENESIS |
Restoration of retinoic acid concentration supresses ethanol-enhanced c-Jun expression and hepatocyte proliferation in rat liver
Gastrointestinal Nutrition Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111, USA and
1 Department of Medicine, Salem Medical Center, Heidelberg, Germany
Chronic and excessive ethanol intake decreases hepatic retinoic acid (RA) concentrations, which may play a critical role in ethanol-induced hyperproliferation in hepatocytes. The present study was conducted to determine whether RA supplementation in chronic ethanol-fed rats could restore hepatic RA concentrations to normal levels and modulate hepatocyte hyperproliferation. Male Sprague–Dawley rats were divided into four groups: control, ethanol-fed, ethanol-fed + 50 µg all-trans-RA/kg body wt and ethanol-fed + 100 µg all-trans-RA/kg body wt. Ethanol was given to rats at 6.2% (v/v) in a liquid diet to provide 36% of total caloric intake. Control animals received the same amount of liquid diet with isocaloric maltodextrin in place of ethanol. Results show that the ethanol treatment in rats for a month significantly increased the mean number of proliferating cell nuclear antigen (PCNA)-positive hepatocytes [4.96 ± 1.36% (ethanol-fed) versus 0.29 ± 0.08% (control), P < 0.05]. This increase was associated with the induction of hepatic c-Jun protein (6.5-fold increase) and cyclin D1 protein (3-fold increase) in ethanol-fed animals as compared with controls. Furthermore, activator protein 1 (AP-1) DNA-binding activity was significantly higher in hepatic nuclear extracts from ethanol-fed rats than those from controls. In contrast, RA supplementation in ethanol-fed rats raised hepatic RA concentration to normal levels and almost completely abolished the ethanol-enhanced c-Jun, cyclin D and AP-1 DNA-binding activities. Moreover, RA supplementation at both doses markedly suppressed the ethanol-induced PCNA-positive hepatocytes by ~80%. These results demonstrate that the restoration of hepatic RA concentrations by dietary RA supplementation suppresses ethanol-induced hepatocyte proliferation via inhibiting c-Jun overexpression, and suggest that RA may play a role in preventing or reversing certain types of ethanol-induced liver injury.
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