FoxO1 Regulates Multiple Metabolic Pathways in the Liver

• DOI: 10.1074/jbc.m600272200
• Publication Date: 2006-02-22T03:42:34Z
• Authors: 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
• Keywords: Lipogenesis; FOXO1; Glucokinase; Gluconeogenesis; Carbohydrate-responsive element-binding protein; Snf3

FoxO transcription factors are important targets of insulin action. To better understand the role proteins in liver, we created transgenic mice expressing constitutively active FoxO1 liver using alpha1-antitrypsin promoter. Fasting glucose levels increased, and tolerance is impaired (TGN) versus wild type (WT) mice. Interestingly, fasting triglyceride cholesterol reduced despite hyperinsulinemia, post-prandial changes markedly suppressed TGN WT Activation pro-lipogenic signaling pathways (atypical protein kinase C B) ability to suppress beta-hydroxybutyrate not TGN. In contrast, de novo lipogenesis measured with (3)H(2)O by approximately 70% after refeeding. Gene-array studies reveal that expression genes involved gluconeogenesis, glycerol transport, amino acid catabolism whereas utilization glycolysis, pentose phosphate shunt, lipogenesis, sterol synthesis WT. Studies adenoviral vectors isolated hepatocytes confirm stimulates gluconeogenic suppresses shunt pathway, including glucokinase SREBP-1c. Together, these results indicate promote hepatic production through multiple mechanisms contribute regulation other metabolic adaptation feeding lipogenic synthetic pathways.