Submitted to: American Journal of Physiology - Gastrointestinal and Liver Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/13/2007
Publication Date: 5/15/2007
Citation: Baumgardner, J., Shankar, K., Korourian, S., Badger, T.M., Ronis, M.J. 2007. Undernutrition enhances alcohol-induced hepatocyte proliferation in the liver of rats fed via total enteral nutrition. American Journal of Physiology Gastrointestinal Liver Physiology. 38(1):355-364.
Interpretive Summary: This report demonstrates the effects of ethanol and undernutrition on alcohol metabolism, in a rat model of alcoholism. We have found that undernutrition did not increase the severity of early liver disease (steatohepatitis) following alcohol; however, when rats were undernourished, alcohol-fed rats had much greater cell division (hepatocyte proliferation). This may be associated with increased long term risk of liver cancer in undernourished compared to well-fed alcoholics. As far as we are aware, this is the first report in the literature demonstrating that undernutrition significantly enhances hepatocyte proliferation in response to chronic alcohol consumption.
Technical Abstract: To assess the relative contributions of undernutrition and ethanol (EtOH) exposure to alcohol-induced hepatotoxicity, female Sprague-Dawley rats were intragastrically infused liquid diets containing 187 kcal/kg3/4/day or 154 kcal/kg3/4/day, with or without 11 g/kg/day EtOH. EtOH clearance was impaired in the 154 kcal/kg3/4/day EtOH group (p < 0.05). A combination of undernutrition and EtOH also increased induction of hepatic cytochrome P450 (CYP) 2E1 and CYP4A1 mRNA, apoprotein and activities (p < 0.05). This was accompanied by increased oxidative stress (p < 0.05). The severity of liver steatosis, macrophage infiltration and focal necrosis was comparable in both EtOH groups. ALT levels were elevated (p < 0.05), but did not differ significantly between the two EtOH groups. TUNEL analysis also demonstrated a comparable increase in apoptosis (p < 0.05). Development of alcohol-induced liver pathology was accompanied by little change in fatty acid (FA) synthesis or degradation at 187 kcal/kg3/4/day, but at 154 kcal/kg3/4/day was accompanied by decreased expression of FA synthesis genes and increased expression of peroxisome proliferator-activated receptor-alpha (PPAR alpha)-regulated FA degradation pathways ( p < 0.05). In addition the 154 kcal/kg3/4/day EtOH group livers exhibited greater hepatocyte proliferation (p < 0.05). We conclude that undernutrition did not exacerbate alcoholic steatohepatitis despite additional oxidative stress produced by an increased induction of CYP2E1 and CYP4A1. However, enhanced ethanol-induced cellular proliferation, perhaps as a result of enhanced PPAR alpha-signaling, may contribute to an increased risk of hepatocellular carcinoma in undernourished alcoholics.