Increased expression and activity of the transcription factor FOXO1 in nonalcoholic steatohepatitis

Luca Valenti, Raffaela Rametta, Paola Dongiovanni, Marco Maggioni, Anna Ludovica Fracanzani, Marco Zappa, Enzo Lattuada, Giancarlo Roviaro, Silvia Fargion

Research output: Contribution to journalArticlepeer-review

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). 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 Ser256 phosphorylation, decreased Akt1, and increased Jun NH2-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.

Original languageEnglish
Pages (from-to)1355-1362
Number of pages8
JournalDiabetes
Volume57
Issue number5
DOIs
Publication statusPublished - May 2008

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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