title: Increased insulin receptor substrate 2 expression is associated with steatohepatitis and altered lipid metabolism in obese subjects.
abstract: OBJECTIVE
  The aim of this study was to evaluate whether dysregulation of molecules involved in FOXO1-dependent insulin signaling in the liver is associated with de novo lipogenesis (DNL) and altered lipid metabolism in severely obese subjects.
  
  
  METHODS
  Observational retrospective study.
  
  
  METHODS
  We considered 71 obese subjects (age 20-68 years; body mass index (BMI)>40 kg m(-2) or BMI>35 kg m(-2) in the presence of metabolic complications) classified into three groups according to liver histology: normal liver (n=12), simple steatosis (n=27) and nonalcoholic steatohepatitis (NASH; n=32). Key nodes in insulin signaling and gene expression of molecules implicated in insulin-dependent glucoregulatory pathway and DNL were evaluated by quantitative real-time PCR and western blotting.
  
  
  RESULTS
  Patients with steatosis had decreased phosphorylation of the insulin kinase AKT1, mediating insulin receptor signaling, and the transcription factor FOXO1, which was therefore more active mediating insulin resistance at transcriptional level. Despite no changes in insulin receptor substrate (IRS)1 mRNA levels, the mRNA and protein levels of the FOXO1 target IRS2 increased progressively with the severity of steatosis from normal liver to NASH. IRS2 expression was correlated with the severity of steatosis, dyslipidemia and liver damage. In patients with NASH, upregulation of IRS2 was associated with preserved activation of AKT2, mediating the stimulating effect of insulin on DNL, and overexpression of its target sterol regulatory element-binding protein 1c (SREBP1c), inducing DNL at transcriptional level. Both FOXO1 and SREBP1c overexpression converged on upregulation of glucokinase, providing substrates for DNL, in NASH patients.
  
  
  CONCLUSIONS
  Differential regulation of IRS1 and IRS2 and of their downstream effectors AKT1 and AKT2 is consistent with upregulation of FOXO1 and may justify the paradoxical state of insulin resistance relative to the glucoregulatory pathway and augmented insulin sensitivity of the liporegulatory pathway typical of steatosis and the metabolic syndrome in obese patients.
authors.affiliation: Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Rametta
authors.forename: E
authors.initials: E
authors.lastname: Mozzi
authors.forename: P
authors.initials: P
authors.lastname: Dongiovanni
authors.forename: B M
authors.initials: BM
authors.lastname: Motta
authors.forename: M
authors.initials: M
authors.lastname: Milano
authors.forename: G
authors.initials: G
authors.lastname: Roviaro
authors.forename: S
authors.initials: S
authors.lastname: Fargion
authors.forename: L
authors.initials: L
authors.lastname: Valenti
mesh_terms: D000328:Adult; D000368:Aged; D015153:Blotting, Western; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D007558:Italy; D050356:Lipid Metabolism; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009767:Obesity, Morbid / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D018384:Oxidative Stress; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger; D060888:Real-Time Polymerase Chain Reaction; D012189:Retrospective Studies; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D012333:RNA, Messenger; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt