Increased Expression and Activity of the Transcription Factor FOXO1 in Nonalcoholic Steatohepatitis
- Luca Valenti1,
- Raffaela Rametta1,
- Paola Dongiovanni1,
- Marco Maggioni2,
- Anna Ludovica Fracanzani1,
- Marco Zappa3,
- Enzo Lattuada3,
- Giancarlo Roviaro3 and
- Silvia Fargion1
- 1Department of Internal Medicine, Ospedale Maggiore Policlinico Mangiagalli Regina Elena IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), University of Milan, Milan, Italy
- 2Department Pathology, Hospital San Paolo, Milan, Italy
- 3Department of Surgery, Ospedale Maggiore Policlinico Mangiagalli Regina Elena IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), University of Milan, Milan, Italy
- Corresponding author: Prof. Silvia Fargion, Department of Internal Medicine, UO Medicina Interna IB, University of Milano Fondazione Policlinico Mangiagalli e Regina Elena IRCCS, Via F Sforza 35, 20122 Milano, Italy. E-mail: silvia.fargion{at}unimi.it
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.
CONCLUSIONS—FOXO1 expression and activity are increased in patients with steatohepatitis, and mRNA levels are correlated with hepatic insulin resistance.
Footnotes
-
Published ahead of print at http://diabetes.diabetesjournals.org on 3 March 2008. DOI: 10.2337/db07-0714.
-
C/EBPα, CAAAT/enhancer-binding protein-α; CREB, cAMP response element–binding protein; FOXO, forkhead box–containing protein O subfamily-1; G6PC, glucose-6-phosphatase catalytic subunit; HCV, hepatitis C virus; HNF, hepatocyte nuclear factor; HOMA-IR, homeostasis model assessment of insulin resistance; JNK, Jun NH2-terminal kinase; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; PGC-1α, peroxisome proliferator–activated receptor- γ coactivator 1α; PPAR, peroxisome proliferator–activated receptor; SOD, superoxide dismutase.
-
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
-
- Accepted January 28, 2008.
- Received May 25, 2007.
- DIABETES
