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 boxcontaining 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). RESEARCH DESIGN AND 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.

Hepatitis C and Alcohol Exacerbate Liver Injury by Suppression of FOXO3

“…37 HCV infection was shown to contribute to insulin resistance by increased FOXO1 activity, 20,38 and a similar observation has been made for nonalcoholic steatohepatitis. 39 It has more recently been shown that FOXO3 activity is increased by starvation/malnutrition in HCV infection, where it modulates innate immunity signaling. 21 These findings underline the importance of FOXO3 in the hepatic response to various stress stimuli.…”

Risk of nonalcoholic steatohepatitis and fibrosis in patients with nonalcoholic fatty liver disease and low visceral adiposity

“…Our results indicate that waist circumference, an easily available surrogate marker of visceral adiposity, was strongly correlated with metabolic alterations and severity of steatosis, but not with NASH and liver fibrosis. We conclude that not yet elucidated mechanisms, including genetic factors [18], [19], [20], [21], [22] and [23] not quantifiable by the simple measure of waist circumference, are responsible for liver disease progression in patients with NAFLD and that the risk of severe liver damage should not be underestimated in lean subjects.…”

Hepatic adiponectin receptors (ADIPOR) 1 and 2 mRNA and their relation to insulin resistance in obese humans

“…FOXO1 mRNA did not differ significantly between groups (14.46 (8.70) and 14.70 (11.87) arbitrary units in the low and the high HOMA-IR groups, respectively). As increased expression and activity of FOXO1 has been associated with NASH 30 and NASH is strongly related to the steatosis score in obese subjects, 31 we determined the relation of hepatic FOXO1 mRNA with steatosis score. Although average values (s.d.)…”