福克斯O1
FOXO3公司
内科学
内分泌学
葡萄糖稳态
生物
胰岛素
蛋白激酶B
胰岛素抵抗
信号转导
医学
细胞生物学
作者
Kebin Zhang,Ling Li,Yajuan Qi,Xiaoping Zhu,Boyi Gan,Ronald A. DePinho,Travis Averitt,Shaodong Guo
出处
期刊:Endocrinology
[The Endocrine Society]
日期:2011-12-07
卷期号:153 (2): 631-646
被引量:158
摘要
Dysregulation of blood glucose and triglycerides are the major characteristics of type 2 diabetes mellitus. We sought to identify the mechanisms regulating blood glucose and lipid homeostasis. Cell-based studies established that the Foxo forkhead transcription factors Forkhead box O (Foxo)-1, Foxo3, and Foxo4 are inactivated by insulin via a phosphatidylinositol 3-kinase/Akt-dependent pathway, but the role of Foxo transcription factors in the liver in regulating nutrient metabolism is incompletely understood. In this study, we used the Cre/LoxP genetic approach to delete the Foxo1, Foxo3, and Foxo4 genes individually or a combination of two or all in the liver of lean or db/db mice and assessed the role of Foxo inactivation in regulating glucose and lipid homeostasis in vivo. In the lean mice or db/db mice, hepatic deletion of Foxo1, rather than Foxo3 or Foxo4, caused a modest reduction in blood glucose concentrations and barely affected lipid homeostasis. Combined deletion of Foxo1 and Foxo3 decreased blood glucose levels, elevated serum triglyceride and cholesterol concentrations, and increased hepatic lipid secretion and caused hepatosteatosis. Analysis of the liver transcripts established a prominent role of Foxo1 in regulating gene expression of gluconeogenic enzymes and Foxo3 in the expression of lipogenic enzymes. Our findings indicate that Foxo1 and Foxo3 inactivation serves as a potential mechanism by which insulin reduces hepatic glucose production and increases hepatic lipid synthesis and secretion in healthy and diabetic states.
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