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Liver-Specific Inhibition of ChREBP Improves Hepatic Steatosis and Insulin Resistance in ob/ob Mice

¹ Institut Cochin, Département d’Endocrinologie, Métabolisme et Cancer, Institut National de la Santé et de la Recherche Médicale (INSERM) U567, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Université René Descartes, Paris, France;
² Unité INSERM U671, Centre de Recherches Biomédicales des Cordeliers, Université Paris VI, Paris, France;
³ Plate-Forme de Micro-Chirurgie de l’Institut Cochin, Paris, France;
⁴ Cardiovascular Research Group, Department of Pediatrics and Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Alberta, Canada

Address correspondence and reprint requests to Catherine Postic, Institut Cochin, Département d’Endocrinologie, Métabolisme et Cancer, 24 rue du Faubourg St. Jacques, Paris 75014, France. E-mail: postic{at}cochin.inserm.fr

Abbreviations: ACC, acetyl-CoA carboxylase; Ad-GFP, GFP adenovirus; Ad-shChREBP, recombinant adenovirus expressing short hairpin RNA against ChREBP; ChREBP, carbohydrate responsive element–binding protein; ERK, extracellular signal–related kinase; FAS, fatty acid synthase; G6Pase, glucose 6-phosphatase; GFP, green fluorescent protein; GK, glucokinase; GPAT, glyceraldehyde 3-phosphate acyltransferase; GSK, glycogen synthase kinase; MAPK, mitogen-activated protein kinase; NAFLD, nonalcoholic fatty liver disease; NEFA, nonesterified fatty acid; shChREBP, short hairpin RNA against ChREBP; shRNA, short hairpin RNA; SCD, stearoyl-CoA desaturase; SREBP, sterol regulatory element–binding protein

Obesity is a metabolic disorder often associated with type 2 diabetes, insulin resistance, and hepatic steatosis. Leptin-deficient (ob/ob) mice are a well-characterized mouse model of obesity in which increased hepatic lipogenesis is thought to be responsible for the phenotype of insulin resistance. We have recently demonstrated that carbohydrate responsive element–binding protein (ChREBP) plays a key role in the control of lipogenesis through the transcriptional regulation of lipogenic genes, including acetyl-CoA carboxylase and fatty acid synthase. The present study reveals that ChREBP gene expression and ChREBP nuclear protein content are significantly increased in liver of ob/ob mice. To explore the involvement of ChREBP in the physiopathology of hepatic steatosis and insulin resistance, we have developed an adenovirus-mediated RNA interference technique in which short hairpin RNAs (shRNAs) were used to inhibit ChREBP expression in vivo. Liver-specific inhibition of ChREBP in ob/ob mice markedly improved hepatic steatosis by specifically decreasing lipogenic rates. Correction of hepatic steatosis also led to decreased levels of plasma triglycerides and nonesterified fatty acids. As a consequence, insulin signaling was improved in liver, skeletal muscles, and white adipose tissue, and overall glucose tolerance and insulin sensitivity were restored in ob/ob mice after a 7-day treatment with the recombinant adenovirus expressing shRNA against ChREBP. Taken together, our results demonstrate that ChREBP is central for the regulation of lipogenesis in vivo and plays a determinant role in the development of the hepatic steatosis and of insulin resistance in ob/ob mice.

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