Increased expression and activity of the transcription factor FOX01 in nonalcoholic steatohepatitis

OBJECTIVE - Nonalocholic fatty liver, affecting 34% of the U. S. population, is characterized by hepatic insulin resistance, which is more marked in the presence of steatolrepatitis, and frequently precedes hyperglycenria. 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 0 subfamily-1 (FOXO 1), a transcription factor that mediates the effect of insulin on the gluconeogenic genes PEPCK and glucose-6-phosphatase catalytic subunit (G6PC). RESEARCH DESIGN AND METHODS-FOXOI, PEPCK, and G6PC mRNA levels were evaluated in 84 subjects: 26 with steatoliepatitis, 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 steatolrepatitis compared with steatosis alone and normal liver, and it was correlated with the homeostasis model assessment of insulin resistance (HOMA-IR) index. FOXO 1 mRNA levels were higher in steatohepatitis, correlated with PEPCK and G6PC mRNA and with HOMA-IR. FOXO1 upregulation was confirmed at protein levels in steatoliepatitis and, in the presence of oxidative stress, was associated with decreased Ser(256) phosphorylation, decreased Akt1, and increased Jun NH2-terminal kinase-1 activity. Consistently, immurrohistochemistry showed increased FOXO1 expression and nuclear localization in steatolrepatitis. FOXO1 mRNA levels correlated with nonalcoholic steatoliepatitis activity score and were modulated by drugs counteracting hepatic lipogenesis. CONCLUSIONS-FOXO1 expression and activity are increased in patients with steatolrepatitis, and mRNA levels are correlated with hepatic insulin resistance.