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J. Biol. Chem., Vol. 280, Issue 33, 29971-29979, August 19, 2005

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The Farnesoid X Receptor Modulates Hepatic Carbohydrate Metabolism during the Fasting-Refeeding Transition^*

Daniel Duran-Sandoval¶, Bertrand Cariou, Fredéric Percevault, Nathalie Hennuyer, Aldo Grefhorst||, Theo H. van Dijk||, Frank J. Gonzalez**, Jean-Charles Fruchart, Folkert Kuipers||, and Bart Staels

From the U.R. 545 INSERM, Atherosclerosis Department, Pasteur Institute of Lille and the Faculty of Pharmacy, Lille2 University, Lille, France, the ^||Center for Liver, Digestive and Metabolic Diseases, Laboratory of Pediatrics, University Hospital, Groningen, The Netherlands, and the ^**Laboratory of Metabolism, Division of Basic Sciences, NCI, National Institutes of Health, Bethesda, Maryland 20892

The liver plays a central role in the control of blood glucose homeostasis by maintaining a balance between glucose production and utilization. The farnesoid X receptor (FXR) is a bile acid-activated nuclear receptor. Hepatic FXR expression is regulated by glucose and insulin. Here we identify a role for FXR in the control of hepatic carbohydrate metabolism. When submitted to a controlled fasting-refeeding schedule, FXR^-/- mice displayed an accelerated response to high carbohydrate refeeding with an accelerated induction of glycolytic and lipogenic genes and a more pronounced repression of gluconeogenic genes. Plasma insulin and glucose levels were lower in FXR^-/- mice upon refeeding the high-carbohydrate diet. These alterations were paralleled by decreased hepatic glycogen content. Hepatic insulin sensitivity was unchanged in FXR^-/- mice. Treatment of isolated primary hepatocytes with a synthetic FXR agonist attenuated glucose-induced mRNA expression as well as promoter activity of L-type pyruvate kinase, acetyl-CoA carboxylase 1, and Spot14. Moreover, activated FXR interfered negatively with the carbohydrate response elements regions. These results identify a novel role for FXR as a modulator of hepatic carbohydrate metabolism.

Received for publication, February 22, 2005 , and in revised form, May 5, 2005.

^* This work was supported in part by the FEDER-Conseil Régional Nord-Pas de Calais Génopole 01360124 and the Fondation Leducq. 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.

Both authors contributed equally to this manuscript.

^¶ Holds a scholarship from the Ministerio de Hacienda del Gobierno de Chile.

To whom correspondence should be addressed: U.R. 545 INSERM-Institut Pasteur de Lille, 1, rue du Professeur Calmette-BP245, 59019 Lille, France. Tel.: 33-3-20-87-73-88; Fax: 33-3-20-87-71-98; E-mail: bart.staels{at}pasteur-lille.fr.

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