title: Limited therapeutic effect of N-acetylcysteine on hepatic insulin resistance in an experimental model of alcohol-induced steatohepatitis.
abstract: BACKGROUND
  Alcohol-related steatohepatitis is associated with increased oxidative stress, DNA damage, lipotoxicity, and insulin resistance in liver. As inflammation and oxidative stress can promote insulin resistance, effective treatment with antioxidants, for example, N-acetylcysteine (NAC), may restore ethanol-impaired insulin signaling in the liver.
  
  
  METHODS
  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, cytokine activation, and insulin/IGF-1 signaling assays.
  
  
  RESULTS
  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 microvesicular to a mainly macrovesicular histological pattern, reduced pro-inflammatory cytokine gene expression, ceramide load, and acid sphingomyelinase activity, and increased expression of IGF-1 receptor and IGF-2 in liver. However, NAC did not abrogate ethanol-mediated impairments in signaling through insulin/IGF-1 receptors, IRS-1, Akt, GSK-3β, or p70S6K, nor did it significantly reduce pro-ceramide or GM3 ganglioside gene expression in liver.
  
  
  CONCLUSIONS
  Antioxidant treatments reduce the severity of chronic alcohol-related steatohepatitis, possibly because of the decreased expression of inflammatory mediators and ceramide accumulation, but they do not restore insulin/IGF-1 signaling in liver, most likely due to persistent elevation of GM3 synthase expression. Effective treatment of alcohol-related steatohepatitis most likely requires dual targeting of oxidative stress and insulin/IGF resistance.
authors.affiliation: Department of Medicine, Brown University, Providence, Rhode Island, USA.
authors.forename: Mashiko
authors.initials: M
authors.lastname: Setshedi
authors.forename: Lisa
authors.initials: L
authors.lastname: Longato
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Petersen
authors.forename: Martin
authors.initials: M
authors.lastname: Ronis
authors.forename: William C
authors.initials: WC
authors.lastname: Chen
authors.forename: Jack R
authors.initials: JR
authors.lastname: Wands
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: de la Monte
mesh_terms: D000111:Acetylcysteine / Q000627:therapeutic use*; D000437:Alcoholism / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005235:Fatty Liver, Alcoholic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007333:Insulin Resistance; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016207:Cytokines; D000111:Acetylcysteine