Increased insulin receptor substrate 2 expression is associated with steatohepatitis and altered lipid metabolism in obese subjects

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. Design: Observational retrospective study. Subjects: 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. Conclusion: 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.