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Diabetes Publish Ahead of Print published online ahead of print March 3, 2008
DOI: 10.2337/db07-0714
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Original Research

INCREASED EXPRESSION AND ACTIVITY OF THE TRANSCRIPTION FACTOR FOXO1 IN NONALCOHOLIC STEATOHEPATITIS

Luca Valenti, MD1, Raffaela Rametta, PhD1, Paola Dongiovanni, PhD1, Marco Maggioni, MD2, Anna Ludovica Fracanzani, MD1, Marco Zappa, MD3, Enzo Lattuada, MD3, Giancarlo Roviaro, MD3, and Silvia Fargion, MD1

From the 1Department of Internal Medicine, Ospedale Maggiore Policlinico Mangiagalli Regina Elena IRCCS, University of Milano
2Department Pathology, H San Paolo, Milano
3Department of Surgery, Ospedale Maggiore Policlinico Mangiagalli Regina Elena IRCCS, University of Milano, all in Milano, Italy. Authors declare that they do not have conflicts of interest relevant to this paper

Objective: Nonalcoholic fatty liver, affecting 34% of the US 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 under definition and have not been evaluated in humans. Aim was to evaluate the relationship between the expression and regulation of the transcription factor FOXO1, which mediates the effect of insulin on the gluconeogenic genes PEPCK and G6PC, and insulin resistance.

Research Design and Methods: FOXO1, PEPCK and G6PC mRNA levels were evaluated in 86 subjects: 26 steatohepatitis, 28 steatosis alone, 14 normal liver histology without metabolic alterations, and 16 HCV chronic hepatitis, 8 with and 8 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 to steatosis alone and normal liver, and correlated with the HOMA-R index. FOXO1 mRNA levels were higher in steatohepatitis, correlated with PEPCK and G6PC mRNA, and with HOMA-R. 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 JNK1 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.

Correspondence: silvia.fargion{at}unimi.it


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