title: Apoptosis and insulin resistance in liver and peripheral tissues of morbidly obese patients is associated with different stages of non-alcoholic fatty liver disease.
abstract: OBJECTIVE
  Non-alcoholic fatty liver disease (NAFLD) is associated with insulin resistance and characterised by different degrees of hepatic lesion. Its pathogenesis and correlation with apoptosis and insulin resistance in insulin target tissues remains incompletely understood. We investigated how insulin signalling, caspase activation and apoptosis correlate with different NAFLD stages in liver, muscle and visceral adipose tissues.
  
  
  METHODS
  Liver, muscle and adipose tissue biopsies from 26 morbidly obese patients undergoing bariatric surgery were grouped according to the Kleiner-Brunt scoring system into simple steatosis, and less severe and more severe non-alcoholic steatohepatitis (NASH). Apoptosis was assessed by DNA fragmentation, and caspase-2 and -3 activation. Insulin signalling and c-Jun NH(2)-terminal kinase (JNK) proteins were evaluated by western blot.
  
  
  RESULTS
  Caspase-3 and -2 activation, and DNA fragmentation were markedly increased in the liver of patients with severe NASH vs in that of those with simple steatosis (p < 0.01). Muscle tissue, and to a lesser extent the liver, had decreased tyrosine phosphorylated insulin receptor and insulin receptor substrate in patients with severe NASH, compared with those with simple steatosis (p < 0.01 muscle; p < 0.05 liver). Concomitantly, Akt phosphorylation decreased in muscle, liver and visceral adipose tissues in patients with severe NASH (at least p < 0.05). Finally, JNK phosphorylation was significantly increased in muscle (p < 0.01) and liver (p < 0.05) from NASH patients, compared with tissue from those with simple steatosis.
  
  
  CONCLUSIONS
  Our results demonstrate a link between apoptosis, insulin resistance and different NAFLD stages, where JNK and caspase-2 may play a key regulatory role.
authors: Research Institute for Medicines and Pharmaceutical Sciences, Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
authors: D M S
authors: DM
authors: Ferreira
authors: R E
authors: RE
authors: Castro
authors: M V
authors: MV
authors: Machado
authors: T
authors: T
authors: Evangelista
authors: A
authors: A
authors: Silvestre
authors: A
authors: A
authors: Costa
authors: J
authors: J
authors: Coutinho
authors: F
authors: F
authors: Carepa
authors: H
authors: H
authors: Cortez-Pinto
authors: C M P
authors: CM
authors: Rodrigues
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000502:physiology*; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D007333:Insulin Resistance / Q000502:physiology*; D050152:Intra-Abdominal Fat / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity / Q000378:metabolism* / Q000473:pathology*