Role of Txnip in adapting fuel metabolism to nutritional state

Txnip 在使燃料代谢适应营养状态中的作用

基本信息

批准号：
7693165
负责人：
Simon To-Yuen Hui
金额：
$ 14.95万
依托单位：
SAN DIEGO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-26 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7693165
关键词：
1-Phosphatidylinositol 4-Kinase Ablation Active Sites Affect Attenuated Binding Cell Proliferation Cell Survival Chloroplasts Cholecalciferol Chromosomes Cysteine Data Disulfides Electron Transport Energy Metabolism Enzymes Exhibits Extrahepatic Fasting First Name Fructose-1,6-Bisphosphatase Gene Expression Genes Glucose Growth Growth Factor Receptors HL-60 Cells Hepatic Injury Insulin Ketone Bodies Knockout Mice Link Lipolysis Liver Mediating Mediator of activation protein Metabolic Metabolism Mitochondria Molecular Weight Mouse Strains Mus Myocardium NADH NADP Names Nonsense Mutation Nutritional Oxidation-Reduction Oxidative Stress PTEN gene Phenotype Phosphatidylinositols Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Play Production Proteins Receptor Signaling Recombinants Recommendation Relative (related person)Research Respiration Role Screening procedure Signal Pathway Signal Transduction Skeletal Muscle Study Section Sulfhydryl Compounds Thinking Thioredoxin Tissues Transcriptional Activation Triglycerides Tumor Suppressor Proteins Up-Regulation Very low density lipoprotein Yeasts abstracting congenic disulfide bond reduction fatty acid oxidation inhibitor/antagonist insight insulin signaling interest lipoprotein lipase novel oxidation phosphatidylinositol 3,4,5-triphosphate prevent respiratory response size very low density lipoprotein triglyceride yeast two hybrid system

项目摘要

Project Summary/Abstract Studies completed since the first submission of this application show that the thioredoxin-NADP(H) inhibitor Txnip provides a mechanistic link between mitochondrial respiration and Akt-PTEN downstream signaling by controlling the reduction of disulfide bonds at the active site of PTEN and thus affects the phosphorylation state of Akt, a key regulator of insulin signaling, cell proliferation and cell survival. Signals regulating metabolism and growth are coordinately integrated via the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. The pool size of phosphatidylinositol 3,4,5-trisphosphate (PIP3), is regulated by the relative activities of PI3K and the phosphoinositide 3-phosphatase PTEN. Inactivation of a small fraction of PTEN via oxidation of critical cysteines in its active site, amplifies insulin and growth factor receptor signaling via expansion of the PIP3 pool, which activates Akt. Following PTEN's rapid reactivation via thioredoxin NADP(H)-mediated disulfide reduction, the transiently amplified PIP3 signal is attenuated by the phosphoinositide 3-phosphatase activity. Our proposed studies will examine the hypothesis that Txnip provides a proximal link between cellular redox state and Akt downstream metabolic and growth regulatory targets by maintaining NADP(H) reductive reactivation of PTEN by achieving the following specific aims: 1) To examine the hypothesis that Txnip ablation inhibits thioredoxin NADPH-dependent reactivation of PTEN by increasing cellular content NADH:NADPH ratio. We hypothesize that in non-lipogenic, oxidative tissue (skeletal muscle and hearts), due to their reduced capacity to produce NADPH, relatively small increases in NADH, caused by reduced mitochondrial respiratory electron transport, causes increases in cellular NADH: NADPH that are sufficient to inhibit the ability of thioredoxin to reduce and reactivate oxidized PTEN. 2) To elucidate the mechanism(s) by which Txnip ablation leads to impaired mitochondrial fuel oxidation 3) To examine the hypothesis that impaired mitochondrial fatty acid oxidation prevents appropriate fasting induced up-regulation of LPL gene expression in skeletal muscle and hearts of Txnip knockout mice. 4) To examine the hypothesis that impaired triglyceride lipolysis in extrahepatic tissues of Txnip knockout mice re-directs the export of hepatic fuel from VLDL triglycerides to glucose and ketone bodies. Achieving these specific aim will provide novel insights elucidating the role of Txnip in adapting fuel metabolism to nutritional state.

项目概要/摘要自首次提交本申请以来完成的研究表明，硫氧还蛋白-NADP(H)抑制剂 Txnip 通过以下方式提供线粒体呼吸和 Akt-PTEN 下游信号传导之间的机制联系控制 PTEN 活性位点二硫键的还原，从而影响磷酸化状态 Akt 是胰岛素信号传导、细胞增殖和细胞存活的关键调节因子。调节新陈代谢的信号和生长通过磷酸肌醇 3-激酶 (PI3K)/Akt 信号通路协调整合。泳池磷脂酰肌醇 3,4,5-三磷酸 (PIP3) 的大小受 PI3K 和磷酸肌醇3-磷酸酶PTEN。通过关键的氧化作用使一小部分 PTEN 失活其活性位点的半胱氨酸通过扩大 PIP3 池来放大胰岛素和生长因子受体信号传导，从而激活 Akt。 PTEN 通过硫氧还蛋白 NADP(H) 介导的二硫键快速重新激活减少，瞬时放大的 PIP3 信号被磷酸肌醇 3-磷酸酶活性减弱。我们提出的研究将检验 Txnip 提供细胞氧化还原之间的近端联系的假设通过维持 NADP(H) 还原性来调节状态和 Akt 下游代谢和生长调节目标通过实现以下具体目标来重新激活 PTEN： 1) 检验 Txnip 消融抑制硫氧还蛋白 NADPH 依赖性再激活的假设 PTEN 通过增加细胞内 NADH:NADPH 的比例来实现。我们假设在非脂肪生成中，氧化组织（骨骼肌和心脏），由于其产生 NADPH 的能力降低，由于线粒体呼吸电子传递减少，导致 NADH 相对较小地增加，引起细胞 NADH：NADPH 的增加，足以抑制硫氧还蛋白的能力还原并重新激活氧化的 PTEN。 2) 阐明 Txnip 消融导致线粒体燃料氧化受损的机制 3) 检验线粒体脂肪酸氧化受损阻碍适当禁食的假设诱导 Txnip 敲除小鼠骨骼肌和心脏中 LPL 基因表达上调。 4)检验Txnip敲除肝外组织中甘油三酯脂解受损的假设小鼠将肝脏燃料的输出从极低密度脂蛋白甘油三酯重新定向为葡萄糖和酮体。实现这些具体目标将提供新的见解，阐明 Txnip 在调整燃料方面的作用新陈代谢到营养状态。