Regulation of Hepatic Gene Expression and Metabolism by FoxO Proteins

描述(由申请人提供)： FOXO Forkhead转录因子是胰岛素作用的主要靶点，可能在糖尿病的发病机制中发挥重要作用，糖尿病是退伍军人发病和死亡的主要原因。FOXO蛋白在促进肝脏葡萄糖生成方面起着重要作用，而胰岛素抑制FOXO活性的能力被认为是维持葡萄糖稳态的重要因素。在转基因小鼠的研究基础上，我们报告了FoxO蛋白也有助于调节肝脏的其他代谢功能，包括脂肪代谢，最近在敲除和敲除模型中的研究支持这一概念。我们先前发现，转基因表达具有结构性活性的FoxO1抑制了SREBP-1c(造脂基因表达的主要调节因子)的表达和进食后的从头脂肪生成(用~3H标记的H2O测量)，但介导这一作用的机制尚不清楚。基于最近的发现，我们已经确定了一种新的机制，有望为介导FoxO对脂代谢影响的途径提供新的线索。计划进行更多的研究，以探讨FoxO蛋白对肝脏中基因表达和新陈代谢的调节作用的具体机制。

DESCRIPTION (provided by applicant): FoxO Forkhead transcription factors are major targets of insulin action and may play an important role in the pathogenesis of diabetes mellitus, a major cause of morbidity and mortality in the Veteran population. FoxO proteins play an important role in promoting hepatic glucose production, and the ability of insulin to suppress FoxO activity is thought to be important in maintaining glucose homeostasis. Based on studies in transgenic mice, we reported that FoxO proteins also contribute to the regulation of other metabolic functions in the liver, including lipd metabolism, and recent studies in knock in and knock out models support this concept. We previously found that transgenic expression of constitutively active FoxO1 suppressed the expression of SREBP-1c (a master regulator of lipogenic gene expression) and de novo lipogenesis (measured with 3H- tagged H2O) after eating, yet the mechanisms mediating this effect remain unclear. Based on recent findings, we have identified a novel mechanism that promises to shed new light onto the pathway mediating FoxO effects on lipid metabolism. Additional studies are planned to investigate specific mechanisms mediating effects of FoxO proteins on gene expression and metabolism in the liver.