Regulation of Hepatic Gene Expression and Metabolism by FoxO Proteins

FoxO 蛋白对肝脏基因表达和代谢的调节

• 批准号: 8443109
• 负责人: Terry G. Unterman
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8443109
• 关键词: ADD-1 protein; Address; Adipose tissue; Anabolism; Catabolism; Development; Diabetes Mellitus; Disease; Eating; Fasting; Fatty acid glycerol esters; Gene Expression; Gene Proteins; Genes; Gluconeogenesis; Hepatic; Hepatocyte; In Vitro; Insulin; Knock-in Mouse; Knock-out; Label; Laboratories; Lead; Light; Lipase; Lipids; Lipolysis; Liver; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molecular; Morbidity - disease rate; Muscle; Pathogenesis; Pathway interactions; Play; Population; Process; Proteins; Regulation; Reporting; Research; Role; Signal Pathway; Switch Genes; Tissues; Transgenic Mice; Transgenic Organisms; Triglycerides; Veterans; Wild Type Mouse; base; blood glucose regulation; fatty acid oxidation; feeding; forkhead protein; glucose metabolism; glucose production; in vivo; inhibitor/antagonist; insight; lipid biosynthesis; lipid disorder; lipid metabolism; mortality; novel; public health relevance; response; transcription factor

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.

描述（由申请人提供）： Foxo Forkhead转录因子是胰岛素作用的主要靶标，并且可能在糖尿病的发病机理中起重要作用，这是退伍军人人口发病率和死亡率的主要原因。 FOXO蛋白在促进肝葡萄糖产生中起着重要作用，胰岛素抑制FOXO活性的能力在维持葡萄糖稳态中很重要。根据对转基因小鼠的研究，我们报道说，FOXO蛋白还有助于调节肝脏中其他代谢功能，包括LIPD代谢，以及最近在敲门和敲除模型中的研究支持了这一概念。我们先前发现，组成型活性FOXO1的转基因表达抑制了SREBP-1C（脂肪生成基因表达的主要调节剂）和从头脂肪形成（用3H标记的H2O测量）的表达，但是介导这种效果的机制仍不清楚。根据最近的发现，我们确定了一种新型机制，该机制有望将新的光芒放到介导Foxo对脂质代谢的影响的途径上。计划进行其他研究，以研究介导FOXO蛋白对肝脏基因表达和代谢的影响的特定机制。