title: Increased expression and activity of the transcription factor FOXO1 in nonalcoholic steatohepatitis.
abstract: OBJECTIVE
  Nonalcoholic fatty liver, affecting 34% of the U.S. population, is characterized by hepatic insulin resistance, which is more marked in the presence of steatohepatitis, and frequently precedes hyperglycemia. The molecular mechanisms underlying the relationship between fatty liver and insulin resistance are still undergoing definition and have not been evaluated in humans. Our aim was to evaluate the relationship between insulin resistance and the expression and regulation of forkhead box-containing protein O subfamily-1 (FOXO1), a transcription factor that mediates the effect of insulin on the gluconeogenic genes PEPCK and glucose-6-phosphatase catalytic subunit (G6PC).
  
  
  METHODS
  FOXO1, PEPCK, and G6PC mRNA levels were evaluated in 84 subjects: 26 with steatohepatitis, 28 with steatosis alone, 14 with normal liver histology without metabolic alterations, and 16 with hepatitis C virus chronic hepatitis, of whom 8 were with and 8 were without steatosis. Protein expression and regulation of FOXO1 and upstream insulin signaling were analyzed in a subset. RESULTS; Expression of PEPCK was higher in steatohepatitis compared with steatosis alone and normal liver, and it was correlated with the homeostasis model assessment of insulin resistance (HOMA-IR) index. FOXO1 mRNA levels were higher in steatohepatitis, correlated with PEPCK and G6PC mRNA and with HOMA-IR. FOXO1 upregulation was confirmed at protein levels in steatohepatitis and, in the presence of oxidative stress, was associated with decreased Ser(256) phosphorylation, decreased Akt1, and increased Jun NH(2)-terminal kinase-1 activity. Consistently, immunohistochemistry showed increased FOXO1 expression and nuclear localization in steatohepatitis. FOXO1 mRNA levels correlated with nonalcoholic steatohepatitis activity score and were modulated by drugs counteracting hepatic lipogenesis.
  
  
  CONCLUSIONS
  FOXO1 expression and activity are increased in patients with steatohepatitis, and mRNA levels are correlated with hepatic insulin resistance.
authors.affiliation: Department of Internal Medicine, Ospedale Maggiore Policlinico Mangiagalli Regina Elena IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), University of Milan, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Valenti
authors.forename: Raffaela
authors.initials: R
authors.lastname: Rametta
authors.forename: Paola
authors.initials: P
authors.lastname: Dongiovanni
authors.forename: Marco
authors.initials: M
authors.lastname: Maggioni
authors.forename: Anna Ludovica
authors.initials: AL
authors.lastname: Fracanzani
authors.forename: Marco
authors.initials: M
authors.lastname: Zappa
authors.forename: Enzo
authors.initials: E
authors.lastname: Lattuada
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Roviaro
authors.forename: Silvia
authors.initials: S
authors.lastname: Fargion
mesh_terms: D000328:Adult; D000368:Aged; D001706:Biopsy; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism / Q000601:surgery; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D005943:Gluconeogenesis; D006801:Humans; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D012333:RNA, Messenger