Restoration of retinoic acid concentration suppresses ethanol-enhanced c-Jun expression and hepatocyte proliferation in rat liver.
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 microg all-trans-RA/kg body wt and ethanol-fed + 100 microg 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 approximately 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.
Chung
J
J
Gastrointestinal Nutrition Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111, USA.
Liu
C
C
Smith
D E
DE
Seitz
H K
HK
Russell
R M
RM
Wang
X D
XD
D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D000431:Ethanol / Q000494:pharmacology*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects*; D007150:Immunohistochemistry; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014212:Tretinoin / Q000378:metabolism*
D016755:Proto-Oncogene Proteins c-jun; D000431:Ethanol; D014212:Tretinoin