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As inflammation and oxidative stress can promote insulin resistance, effective treatment with antioxidants, for example, N\u2010acetylcysteine (NAC), may restore ethanol\u2010impaired insulin signaling in the liver.<\/jats:p><jats:p><jats:bold>Methods:\u2002<\/jats:bold> Adult male Sprague\u2013Dawley rats were fed for 130\u2003days with liquid diets containing 0 or 37% ethanol by caloric content, and simultaneously treated with vehicle or NAC. Chow\u2010fed controls were studied in parallel. Liver tissues were used for histopathology, cytokine activation, and insulin\/IGF\u20101 signaling assays.<\/jats:p><jats:p><jats:bold>Results:\u2002<\/jats:bold> We observed significant positive trends of increasing severity of steatohepatitis (<jats:italic>p<\/jats:italic>\u2003=\u20030.016) with accumulation of neutral lipid (<jats:italic>p<\/jats:italic>\u2003=\u20030.0002) and triglycerides (<jats:italic>p<\/jats:italic>\u2003=\u20030.0004) from chow to control, to the ethanol diet, irrespective of NAC treatment. In ethanol\u2010fed rats, NAC reduced inflammation, converted the steatosis from a predominantly microvesicular to a mainly macrovesicular histological pattern, reduced pro\u2010inflammatory cytokine gene expression, ceramide load, and acid sphingomyelinase activity, and increased expression of IGF\u20101 receptor and IGF\u20102 in liver. However, NAC did not abrogate ethanol\u2010mediated impairments in signaling through insulin\/IGF\u20101 receptors, IRS\u20101, Akt, GSK\u20103\u03b2, or p70S6K, nor did it significantly reduce pro\u2010ceramide or GM3 ganglioside gene expression in liver.<\/jats:p><jats:p><jats:bold>Conclusions:\u2002<\/jats:bold> Antioxidant treatments reduce the severity of chronic alcohol\u2010related steatohepatitis, possibly because of the decreased expression of inflammatory mediators and ceramide accumulation, but they do not restore insulin\/IGF\u20101 signaling in liver, most likely due to persistent elevation of GM3 synthase expression. Effective treatment of alcohol\u2010related steatohepatitis most likely requires dual targeting of oxidative stress and insulin\/IGF resistance.<\/jats:p>","DOI":"10.1111\/j.1530-0277.2011.01569.x","type":"journal-article","created":{"date-parts":[[2011,7,26]],"date-time":"2011-07-26T17:57:03Z","timestamp":1311703023000},"page":"2139-2151","source":"Crossref","is-referenced-by-count":39,"title":["Limited Therapeutic Effect of N\u2010Acetylcysteine on Hepatic Insulin Resistance in an Experimental Model of Alcohol\u2010Induced Steatohepatitis"],"prefix":"10.1111","volume":"35","author":[{"given":"Mashiko","family":"Setshedi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Longato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis 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