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1 Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, 72202, United States; Arkansas Children's Nutrition Center, 1120 Marshall Street, Little Rock, Arkansas, 72202, United States
2 Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States; Arkansas Children's Nutrition Center, 1120 Marshall Street, Little Rock, Arkansas, 72202, United States
3 Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States; Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
4 Physiology and Biophysics, University of Arkansas for Medical Science, Little Rock,, Arkansas, United States; Arkansas Children's Nutrition Center, 1120 Marshall Street, Little Rock, Arkansas, 72202, United States
* To whom correspondence should be addressed. E-mail: ronismartinj{at}uams.edu.
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 in the two EtOH groups (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-
(PPAR)-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 does not exacerbate alcoholic steatohepatitis despite additional oxidative stress produced by an increased induction of CYP2E1 and CYP4A1; however, enhanced EtOH-induced cellular proliferation, perhaps as a result of enhanced PPAR-signaling, may contribute to an increased risk of hepatocellular carcinoma in undernourished alcoholics.
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