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J. Biol. Chem., Vol. 281, Issue 15, 10105-10117, April 14, 2006

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FoxO1 Regulates Multiple Metabolic Pathways in the Liver

EFFECTS ON GLUCONEOGENIC, GLYCOLYTIC, AND LIPOGENIC GENE EXPRESSION^*

Wenwei Zhang, Sandip Patil, Balwant Chauhan, Shaodong Guo, David R. Powell^¶, Jamie Le, Angelos Klotsas, Ryan Matika, Xiangshan Xiao, Roberta Franks, Kim A. Heidenreich^||, Mini P. Sajan^**, Robert V. Farese^**, Donna Beer Stolz, Patrick Tso, Seung-Hoi Koo^¶¶||||, Marc Montminy^¶¶, and Terry G. Unterman¹

From the Departments of Medicine and Physiology and Biophysics, University of Illinois College of Medicine, Chicago, Illinois 60612, the Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612, the ^¶Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, the ^||Department of Pharmacology, University of Colorado Health Science Center, Aurora, Colorado 80045, the ^**Research Service, James A. Haley Veterans Medical Center and Department of Internal Medicine, University of South Florida College of Medicine, Tampa, Florida 33612, the Center for Biologic Imaging, Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, the Department of Pathology, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0529, the ^¶¶Peptide Biological Laboratories, Salk Institute for Biological Studies, La Jolla, California 92037-1002, and the ^||||Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea

FoxO transcription factors are important targets of insulin action. To better understand the role of FoxO proteins in the liver, we created transgenic mice expressing constitutively active FoxO1 in the liver using the 1-antitrypsin promoter. Fasting glucose levels are increased, and glucose tolerance is impaired in transgenic (TGN) versus wild type (WT) mice. Interestingly, fasting triglyceride and cholesterol levels are reduced despite hyperinsulinemia, and post-prandial changes in triglyceride levels are markedly suppressed in TGN versus WT mice. Activation of pro-lipogenic signaling pathways (atypical protein kinase C and protein kinase B) and the ability to suppress -hydroxybutyrate levels are not impaired in TGN. In contrast, de novo lipogenesis measured with ³H₂O is suppressed by 70% in the liver of TGN versus WT mice after refeeding. Gene-array studies reveal that the expression of genes involved in gluconeogenesis, glycerol transport, and amino acid catabolism is increased, whereas genes involved in glucose utilization by glycolysis, the pentose phosphate shunt, lipogenesis, and sterol synthesis pathways are suppressed in TGN versus WT. Studies with adenoviral vectors in isolated hepatocytes confirm that FoxO1 stimulates expression of gluconeogenic genes and suppresses expression of genes involved in glycolysis, the shunt pathway, and lipogenesis, including glucokinase and SREBP-1c. Together, these results indicate that FoxO proteins promote hepatic glucose production through multiple mechanisms and contribute to the regulation of other metabolic pathways important in the adaptation to fasting and feeding in the liver, including glycolysis, the pentose phosphate shunt, and lipogenic and sterol synthetic pathways.

Received for publication, January 10, 2006 , and in revised form, February 14, 2006.

^* This work was supported in part by grants from the National Institutes of Health Grants DK41430 (to T. G. U.) and CA76541 (to D. B. S.) and by the Department of Veterans Affairs Merit Review Program (to T. G. U.). FPLC and lipoprotein analyses were performed in the University of Cincinnati Mouse Metabolic Phenotyping Center (Grant DK59630). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4 and Tables S1, S2a, and S2b.

¹ To whom correspondence should be addressed: Jesse Brown Veterans Affairs Medical Center, Room 6229, Medical Research Unit (MP 151), 820 South Damen Ave., Chicago, IL 60612 Tel.: 312-569-7427; Fax: 312-569-8114; E-mail: Unterman{at}uic.edu.

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