Regulation of Hepatic Gene Expression and Metabolism by FoxO Proteins

描述（由申请人提供）： FoxO叉头转录因子是胰岛素作用的主要靶点，并可能在糖尿病的发病机制中发挥重要作用，糖尿病是退伍军人群体发病和死亡的主要原因。FoxO蛋白在促进肝脏葡萄糖产生中起重要作用，并且胰岛素抑制FoxO活性的能力被认为在维持葡萄糖稳态中是重要的。基于在转基因小鼠中的研究，我们报道了FoxO蛋白还有助于调节肝脏中的其他代谢功能，包括lipd代谢，并且最近在敲入和敲除模型中的研究支持了这一概念。我们以前发现，组成型活性FoxO 1的转基因表达抑制SREBP-1c（脂肪生成基因表达的主要调节因子）的表达和进食后的新生脂肪生成（用3 H标记的H2O测量），但介导这种效应的机制仍不清楚。基于最近的研究结果，我们已经确定了一种新的机制，有望为介导FoxO对脂质代谢影响的途径提供新的线索。计划进行更多的研究，以研究FoxO蛋白对肝脏中基因表达和代谢的介导作用的具体机制。

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.