Effects of long-term ethanol administration in a rat total enteral nutrition model of alcoholic liver disease.

Abstract

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.

• Authors: Martin J J Ronis, Leah Hennings, Ben Stewart, Alexei G Basnakian, Eugene O Apostolov, Emanuele Albano, Thomas M Badger, Dennis R Petersen
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 300 Issue 1 Pg. G109-19 (Jan 2011) ISSN: 1522-1547 [Electronic] United States
• PMID: 21051528 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Dietary Fats
• Hedgehog Proteins
• Ethanol
• Cytochrome P-450 Enzyme System
• CYP2F4, rat
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology, therapeutic use)
• Animals
• Cell Proliferation (drug effects)
• Cytochrome P-450 Enzyme System (metabolism)
• Dietary Fats (administration & dosage)
• Enteral Nutrition
• Ethanol (pharmacology, toxicity)
• Fatty Liver (etiology, pathology)
• Hedgehog Proteins (metabolism)
• Lipid Metabolism (drug effects)
• Liver (drug effects, pathology)
• Liver Diseases, Alcoholic (metabolism, pathology)
• Liver Regeneration (drug effects)
• Male
• Oxidative Stress (drug effects)
• Rats