Effects of long-term ethanol administration in a rat total enteral nutrition model of alcoholic liver disease.
Male Sprague-Dawley rats were chronically fed a high-unsaturated-fat diet for 130 days by using total enteral nutrition (TEN), or the same diet in which ethanol (EtOH) isocalorically replaced carbohydrate calories. Additional groups were supplemented with the antioxidant N-acetylcysteine (NAC) at 1.7 g·kg(-1)·day(-1). Relative to an ad libitum chow-fed group, the high-fat-fed controls had three- to fourfold greater expression of fatty acid transporter CD36 mRNA and developed mild steatosis but little other hepatic pathology. NAC treatment resulted in increased somatic growth relative to controls (4.0 ± 0.1 vs. 3.1 ± 0.1 g/day) and increased hepatic steatosis score (3.5 ± 0.6 vs. 2.7 ± 1.2), associated with suppression of the triglyceride hydrolyzing protein adiponutrin, but produced no elevation in serum alanine aminotransferase (ALT). Chronic EtOH treatment increased expression of fatty acid transport protein FATP-2 mRNA twofold, resulting in marked hepatic steatosis, oxidative stress, and a twofold elevation in serum ALT. However, no changes in tumor necrosis factor-α or transforming growth factor-β expression were observed. Fibrosis, as measured by Masson's trichrome and picrosirius red staining, and a twofold increase in expression of type I and type III collagen mRNA, was only observed after EtOH treatment. Long-term EtOH treatment increased hepatocyte proliferation but did not modify the hepatic mRNAs for hedgehog pathway ligands or target genes or genes regulating epithelial-to-mesenchymal transition. Although the effects of NAC on EtOH-induced fibrosis could not be fully evaluated, NAC had additive effects on hepatocyte proliferation and prevented EtOH-induced oxidative stress and necrosis, despite a failure to reverse hepatic steatosis.
epartment of Pharmacology and Toxicology, 2University of Arkansas for Medical Sciences and Arkansas Children's Nutrition Center, Little Rock, Arkansas 72202, USA. RonisMartinJ@uams.edu
Martin J J
MJ
Ronis
Leah
L
Hennings
Ben
B
Stewart
Alexei G
AG
Basnakian
Eugene O
EO
Apostolov
Emanuele
E
Albano
Thomas M
TM
Badger
Dennis R
DR
Petersen
D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage; D004750:Enteral Nutrition; D000431:Ethanol / Q000494:pharmacology / Q000633:toxicity*; D005234:Fatty Liver / Q000209:etiology* / Q000473:pathology; D053823:Hedgehog Proteins / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000378:metabolism* / Q000473:pathology; D008115:Liver Regeneration / Q000187:drug effects; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats
D004041:Dietary Fats; D053823:Hedgehog Proteins; D000431:Ethanol; D003577:Cytochrome P-450 Enzyme System; C497724:CYP2F4, rat; D000111:Acetylcysteine