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, Terry G. Unterman

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331 Citations (Scopus)

Abstract

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 α1-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 β-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.

Original languageEnglish
Pages (from-to)10105-10117
Number of pages13
JournalJournal of Biological Chemistry
Volume281
Issue number15
DOIs
Publication statusPublished - 2006 Apr 14

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Zhang, W., Patil, S., Chauhan, B., Guo, S., Powell, D. R., Le, J., Klotsas, A., Matika, R., Xiao, X., Franks, R., Heidenreich, K. A., Sajan, M. P., Farese, R. V., Stolz, D. B., Tso, P., Koo, S. H., Montminy, M., & Unterman, T. G. (2006). FoxO1 regulates multiple metabolic pathways in the liver effects on gluconeogenic, glycolytic, and lipogenic gene expression. Journal of Biological Chemistry, 281(15), 10105-10117. https://doi.org/10.1074/jbc.M600272200