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Title: Limited theraputic effect of n-acetylcysteine on hepatic insulin resistance in an experimental model of alcohol-induced steatohepatitis

item SETSHEDI, MASHIKO - Brown University
item LONGATO, LISA - Brown University
item PETERSEN, DENNIS - University Of Colorado
item RONIS, MARTIN - Arkansas Children'S Nutrition Research Center (ACNC)
item WANDS, JACK - Brown University
item DE LA MONTE, SUZANNE - Brown University

Submitted to: Alcoholism: Clinical and Experimental
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/28/2011
Publication Date: 12/1/2011
Citation: Setshedi, M., Longato, L., Petersen, D.R., Ronis, M.J., Wands, J.R., De La Monte, S. 2011. Limited theraputic effect of n-acetylcysteine on hepatic insulin resistance in an experimental model of alcohol-induced steatohepatitis. Alcoholism: Clinical and Experimental. 35(12):2139-2151.

Interpretive Summary: Alcoholic liver damage is associated with the appearance of fat in the liver accompanied by inflammation and cell death (steatohepatitis). In addition, we and others have observed inhibited insulin signaling in the livers of alcohol treated rats and patients with liver damage. It has been suggested that the key factor resulting in progression of liver injury from simple fat accumulation to steatohepatitis is oxidative stress. The current study was designed to test the hypothesis that dietary antioxidant treatment would block progression of liver injury as a result of blocking oxidative stress and might be a successful therapy for treatment of alcoholic liver disease. Rats were fed alcohol for 130 d using liquid diets fed via a stomach tube with or without additional treatment with antioxidant N-acetylcysteine (NAC). Alcohol treatment resulted in the expected steatohepatitis with a mixture of large and small lipid droplets in liver sections, cellular injury and inflammation. NAC treatment converted the pattern of fat accumulation to mainly small droplets, prevented the accumulation of ceramide (a toxic lipid metabolite) and partially reduced the severity of liver pathology. However, NAC treatment did not block ethanol inhibition of insulin signaling or increases in inflammatory signaling molecules. These data suggest that blockage of development of both oxidative stress and insulin resistance is required for successful treatment of alcoholic liver injury.

Technical Abstract: Alcohol-related steatohepatitis is associated with increased oxidative stress, DNA damage, lipotoxicity, and insulin resistance in liver. Hypothesis: Since inflammation and oxidative stress can promote insulin resistance, effective treatment with anti-oxidants, e.g. N-acetylcysteine (NAC), may restore ethanol-impaired insulin signaling in the liver. Adult male Sprague-Dawley rats were fed for 130 days with liquid diets containing 0% or 37% ethanol by caloric content, and simultaneously treated with vehicle or NAC. Chow-fed controls were studied in parallel. Liver tissues were used for histopathology, and lipid, cytokine activation, and insulin/IGF-1 signaling assays. We observed significant positive trends of increasing severity of steatohepatitis (P=0.016) with accumulation of neutral lipid (P=0.0002) and triglycerides (P=0.0004) from chow to control, to the ethanol diet, irrespective of NAC treatment. In ethanol-fed rats, NAC reduced inflammation, converted the steatosis from a predominantly micro-vesicular to a mainly macro-vesicular histological pattern, reduced ceramide load, and increased expression of IGF-1 receptor and IGF-2 in liver. However, it did not abrogate ethanol-mediated impairments in signaling through insulin/IGF-1 receptors, IRS-1, Akt, GSK-3 beta, or p70S6K, and it did not reduce pro-inflammatory cytokine levels, pro-ceramide gene expression, or sphingomyelinase activity in liver. Anti-oxidant treatments reduce the severity of chronic alcohol-related steatohepatitis, possibly due to decreased ceramide accumulation, but they do not restore insulin/IGF-1 signaling or quell cytokine activation in liver. Effective treatment of alcohol-related steatohepatitis most likely requires dual targeting of oxidative stress and insulin/IGF resistance.