Location: Arkansas Children's Nutrition CenterTitle: The antioxidant n-acetylcysteine reduced necrosis, but exacerbated liver fibrosis induced by chronic alcohol in rats fed via total enteral nutrition Author
Submitted to: Alcoholism: Clinical and Experimental
Publication Type: Abstract Only
Publication Acceptance Date: 3/15/2009
Publication Date: 6/15/2009
Citation: Ronis, M.J., Ferguson, M.E., Badeaux, J., Blackburn, M.L., Till, R.S., Hennings, L., Stewart, B., Badger, T.M., Petersen, D.R. 2009. The antioxidant n-acetylcysteine reduced necrosis, but exacerbated liver fibrosis induced by chronic alcohol in rats fed via total enteral nutrition [abstract]. Alcoholism: Clinical and Experimental Research. 33(S1):230A. Program No. P879. Interpretive Summary:
Technical Abstract: Despite many years of research, the molecular mechanisms underlying progression of alcoholic liver injury from simple steatosis through steatohepatitis and fibrosis remain in dispute. In the current study male Sprague-Dawley rats (350 g) were chronically fed a high unsaturated fat diet for 120 d using total enteral nutrition (TEN), or a diet in which ethanol (EtOH) isocalorically replaced carbohydrate calories. Additional control and EtOH-treated groups were supplemented with the antioxidant N-acetylcysteine (NAC) at 1.7 g/kg/d. Relative to an ad libitum chow-fed group, chronic feeding of the high-fat TEN diets resulted in development of mild steatosis, but no other hepatic pathology or effects on serum ALT values. Chronic supplementation with NAC resulted in increased somatic growth (P<0.05) and marked increases in hepatic steatosis (P<0.05), but no elevation in serum ALT concentrations. EtOH produced hepatic steatosis, inflammation, and focal necrosis accompanied by 2- to 3-fold elevation in serum ALTs and the appearance of fibrosis (P< 0.05) as determined by both Mason-Trichrome and Picosirius Red staining of collagen. This was accompanied by 2-fold increases in expression of Type 1 and Type 3 collagen mRNA (P< 0.05). Surprisingly, although the combination of EtOH and NAC prevented EtOH-associated decreases in the ratio of reduced to oxidized GSH (P<0.05) and prevented the EtOH-induced increase in serum ALT values, hepatic steatosis was elevated over NAC or EtOH treatment alone, and collagen staining was increased relative to EtOH alone. These data suggest that the TEN model can be utilized to study EtOH-induced fibrosis. Surprisingly, although NAC appeared to be an effective antioxidant and to reduce EtOH-induced necrosis, effects on fibrosis were enhanced and correlated with increases in hepatic steatosis. These data raise interesting questions about the role of oxidative stress in fibrogenesis and the relationship between hepatosteatosis and fibrosis.