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LIVER AND BILIARY TRACT
Departments of 1Pharmacology and Toxicology, 2Physiology and Biophysics, and 3Pathology, University of Arkansas for Medical Sciences; and 4Arkansas Children's Nutrition Center, Little Rock, Arkansas
Submitted 19 January 2007 ; accepted in final form 13 May 2007
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-
(PPAR-)-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- signaling, may contribute to an increased risk of hepatocellular carcinoma in undernourished alcoholics.
ethanol; liver injury; cell proliferation; peroxisome-proliferator activated receptor-
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