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

• 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
• 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

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.

项目摘要/摘要 自本申请的第一次提交以来完成的研究表明，硫氧还蛋白-NADP（H）抑制剂 TXNIP提供了线粒体呼吸与Akt-Pten下游信号之间的机械联系 控制PTEN活跃位点二硫键的还原，从而影响磷酸化状态 Akt的胰岛素信号传导，细胞增殖和细胞存活的关键调节剂。信号调节新陈代谢和 通过磷酸肌醇3-激酶（PI3K）/AKT信号通路协调整合。游泳池 磷脂酰肌醇的大小为3,4,5-三磷酸（PIP3），受PI3K和PI3K的相对活性调节 磷酸肌醇3-磷酸酶PTEN。通过临界的氧化，一小部分PTEN失活 半胱氨酸在其活性部位，通过扩增PIP3池的扩增来放大胰岛素和生长因子受体信号传导， 激活AKT。在PTEN通过硫氧还蛋白NADP（H）介导的二硫化物快速重新激活 还原，瞬时扩增的PIP3信号被磷酸肌醇3-磷酸酶活性减弱。 我们提出的研究将研究以下假设：TXNIP在细胞氧化还原之间提供近端联系 通过保持NADP（H）还原性，状态和AKT下游代谢和生长调节靶标 通过实现以下特定目标来重新激活PTEN： 1）检查txnip消融抑制硫氧还蛋白NADPH依赖性激活的假设 通过增加细胞含量NADH：NADPH比率。我们假设在非脂肪性的， 氧化组织（骨骼肌和心脏），由于其产生NADPH的能力降低， 由线粒体呼吸电子转运降低引起的NADH的增加相对较小， 原因增加了细胞NADH：NADPH，足以抑制硫氧还蛋白的能力 减少和重新激活氧化的PTEN。 2）阐明TXNIP消融导致线粒体燃料氧化受损的机制 3）检查线粒体脂肪酸氧化受损的假设可预防适当的禁食 在骨骼肌和TXNIP基因敲除小鼠心脏中诱导LPL基因表达的上调。 4）检查假设TXNIP基因敲除肝外组织中甘油三酸酯脂解会受损 小鼠将肝燃料从VLDL甘油三酸酯中的出口重新引入到葡萄糖和酮体。 实现这些特定目标将提供新颖的见解，以阐明TXNIP在适应燃料中的作用 代谢为营养状态。