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A more recent version of this article appeared on April 14, 2006 Originally published In Press as doi:10.1074/jbc.M600272200 on February 21, 2006
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Papers In Press, published online ahead of print February 28, 2006
J. Biol. Chem, 10.1074/jbc.M600272200
Submitted on January 10, 2006
Revised on February 14, 2006
Accepted on February 21, 2006

FOXO1 regulates multiple metabolic pathways in the liver: Effects on gluoconeogenic, 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. Unterman

Medicine and Physiology and Biophysics, University of Illinois at Chicago and Jesse Brown VA Medical Center, Chicago, Illinois 60612

Corresponding Author: unterman{at}uic.edu

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 delta 1-antitrypsin promoter. Fasting blood glucose levels are increased despite high insulin levels, and glucose tolerance is impaired in transgenic (TGN) vs. 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 vs. WT mice. Activation of pro-lipogenic signaling pathways (atypical protein kinase C, protein kinase B) and the ability to suppress beta-hydroxybutyrate levels are not impaired in TGN. In contrast, de novo lipogenesis measured with 3H2O is suppressed by ~70% in the liver of TGN vs. WT mice after refeeding. Gene array studies reveal that the expression of genes involved in gluconeogenesis, glycerol transport and amino acid catabolism is increased, while expression of genes involved in glucose utilization by glycolysis, the pentose phosphate shunt, and lipogenic and sterol synthetic pathways is suppressed in TGN vs. WT. Studies in isolated hepatocytes confirm that FoxO1 stimulates expression gluconeogenic genes and suppresses expression of genes involved in glycolysis, the pentose phosphate shunt and lipogenesis, including glucokinase and SREBP-1c. These results indicate that FoxO proteins promote hepatic glucose production through multiple mechanisms, and also 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.


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