Undernutrition enhances alcohol-induced hepatocyte proliferation in the liver of rats fed via total enteral nutrition

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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 or 154 kcal·kg−3/4·day−1 with or without 11 g·kg−1·day−1 EtOH. EtOH clearance was impaired in the 154 kcal·kg−3/4·day−1 EtOH group ( P ≤ 0.05). A combination of undernutrition and EtOH also increased the induction of hepatic cytochrome P-450 (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. Alanine aminotransferase levels were elevated ( P ≤ 0.05) but did not significantly differ between the two EtOH groups. TUNEL analysis also demonstrated a comparable increase in apoptosis in the two EtOH groups ( P ≤ 0.05). The development of alcohol-induced liver pathology was accompanied by little change in fatty acid (FA) synthesis or degradation at 187 kcal·kg−3/4·day−1 but at 154 kcal·kg−3/4·day−1 was accompanied by decreased expression of FA synthesis genes and increased expression of peroxisome proliferator-activated receptor-α (PPAR-α)-regulated FA degradation pathways ( P ≤ 0.05). In addition, 154 kcal·kg−3/4·day−1 EtOH group livers exhibited greater hepatocyte proliferation ( P ≤ 0.05). We conclude that undernutrition does 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-α signaling, may contribute to an increased risk of hepatocellular carcinoma in undernourished alcoholics.