N-Acetylcysteine Attenuates Progression of Liver Pathology in a Rat Model of Nonalcoholic Steatohepatitis 3

Abstract

A “2-hit” model for nonalcoholic steatohepatitis (NASH) has been proposed in which steatosis constitutes the “first hit” and sensitizes the liver to potential “second hits” resulting in NASH. Oxidative stress is considered a candidate for the second hit. N-acetylcysteine (NAC), an antioxidant, has been suggested as a dietary therapy for NASH. We examined the effects of NAC in a rat total enteral nutrition (TEN) model where NASH develops as the result of overfeeding dietary polyunsaturated fat. Male Sprague-Dawley rats consumed pelleted AIN-93G diets ad libitum or were overfed a 9200 kJ·kg−0.75·d−1 liquid diet containing 70% corn oil with or without 2 g·kg−1·d−1 NAC i.g. for 65 d. Hepatic steatosis was not influenced by dietary supplementation with NAC; however, the liver pathology score was lower (P ≤ 0.05) and NAC provided partial protection against alanine aminotransferase release (P ≤ 0.05). NAC attenuated increased hepatic oxidative stress (TBARS; P ≤ 0.05) and prevented increases in cytochrome P450 2E1 apoprotein and mRNA and in tumor necrosis factor-α (TNF α) mRNA. Titers of auto-antibodies against proteins adducted to lipid peroxidation products were lower in serum of the NAC group than in the 70% corn oil group (P ≤ 0.05). NAC also decreased Picosirius red staining of collagen, a marker of fibrosis. However, markers of hepatic stellate cell activation were unaffected. Using NAC in a TEN model of NASH, we have demonstrated that NAC prevents many aspects of NASH progression by decreasing development of oxidative stress and subsequent increases in TNF α but does not block development of steatosis.