Hepatic Insuling Action: Role of the Pentose Cycle

肝脏绝缘作用：戊糖循环的作用

基本信息

批准号：
7617244
负责人：
Irwin Jack Kurland
金额：
$ 9.44万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-03-15 至 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7617244
关键词：
1,2-diacylglycerol ADD-1 protein Acetyl-CoA Carboxylase Activity Cycles Adipose tissue Affect Binding Biochemical Pathway Cells Cytoplasm Data Diglycerides Enzymes Event Fasting Fatty Acids Fatty Liver Fatty-acid synthase Feedback Genes Glucokinase Glucose Glucosephosphate Dehydrogenase Glycerol Glycolysis Grant Hepatic Hepatocyte Homeostasis Hypoglycemia In Vitro Insulin Link Lipids Liver Measures Metabolic Metabolic Pathway Mus NADP Nuclear Nuclear Translocation Nutrient Organ Oxidoreductase Pathway interactions Pentosephosphate Pathway Pentosephosphates Pentoses Phenotype Phosphatidate Phosphatase Phosphatidylinositols Phosphorylation Physiology Protein phosphatase Regulation Research Personnel Role Signal Transduction Systems Biology Tissues Tracer Transcriptional Activation Triglycerides Up-Regulation Xylulose activating transcription factor blood glucose regulation enzyme pathway feeding glucose production human FRAP1 protein in vivo inorganic phosphate insulin signaling lipid biosynthesis lipine mouse model oxidation phosphatidate phosphatidylinositol-3-phosphatase programs receptor response stable isotope synergism transcription factor

项目摘要

DESCRIPTION (provided by applicant): Hepatic insulin action: Role of the pentose cycle. Insulin, after binding to its liver receptor, initiates the activation of a signaling effector chain, via PI3-K/Akt activation, and subsequent mTOR activation, stimulates glycolysis, lipogenesis, and via mTOR, glucose-6-P dehydrogenase (G6PDH) and pentose phosphate pathway (PPP) flux. Our data shows that pentose cycle activity, measured using stable isotope flux phenotyping, is not just a passive response to PI3-K/mTOR activation. In the whole body Pten hetero-deficient mouse , basal glucose and insulin are unchanged, glucokinase (GK) is downregulated in the basal state, PPP flux, and glucose/glucose-6-P flux re-cycling, is not increased in the fasted to fed transition, basal hepatic glucose production is unchanged and excess accumulation of hepatic triglycerides (TGs) does not occur. This is in contrast to the hepatic specific Pten KO, which is characterized by basal hypoglycemia and hepatic steatosis. GK expression is thought to be an indicator of hepatic PI3-K action, so these "paradoxical" responses for GK, PPP flux and TG accumulation for the Pten mouse suggest that regulation of glucose/glucose-6-P cycling, and PPP flux, is important for glucose homeostasis. We contend, and will show that the PPP flux is a vital link in the metabolite feedback control of mTOR/Akt/AMPK signaling. Insulin stimulated PI3-K/Akt activity is known to inhibit HGP, p-oxidation and TG secretion via phosphorylation and translocation to the cytoplasm of nuclear Foxol and FoxA2, and GK. Glycolytic flux induction, and fatty acid (FA) synthesis, is dependent upon the nuclear translocation of SREBP-1c and ChREBP. SREBP-1c and ChREBP synergistically induce lipogenic enzyme expression, and the activation of ChREBP is dependent on the amount of xylulose-5-P (X5P) generated in the PPP. NADPH generated in the PPP is crucial for fatty acid and TG synthesis, and additional metabolite feedback to insulin signaling can be postulated to result from phosphatidate and diacylglycerol generated during TG synthesis. The purpose of this grant is to understand how Pten affects signaling feedback between Akt, AMPK and mTOR, how these signals regulate transcription factor activation/translocation in the fasted and fed states, and finally, how these fasted/fed signaling events are dependent on intra-organ metabolite feedback from the hepatic PPP and glycolytic/TG synthesis pathways, and inter-organ flux regulatory mechanisms.

描述（由申请人提供）：肝胰岛素作用：戊糖循环的作用。胰岛素与其肝脏受体结合后，通过 PI3-K/Akt 激活和随后的 mTOR 激活，启动信号传导效应链的激活，并通过 mTOR、葡萄糖-6-P 脱氢酶 (G6PDH) 和 mTOR 刺激糖酵解和脂肪生成。磷酸戊糖途径（PPP）通量。我们的数据表明，使用稳定同位素通量表型测量测量的戊糖循环活性不仅仅是对 PI3-K/mTOR 激活的被动反应。在全身Pten杂缺陷小鼠中，基础葡萄糖和胰岛素没有变化，葡萄糖激酶（GK）在基础状态下下调，PPP通量和葡萄糖/葡萄糖-6-P通量再循环，在禁食状态下不增加到进食过渡时，基础肝葡萄糖产量没有变化，并且不会发生肝甘油三酯（TG）的过量积累。这与肝脏特异性 Pten KO 形成鲜明对比，后者的特征是基础低血糖和肝脂肪变性。 GK 表达被认为是肝脏 PI3-K 作用的指标，因此 Pten 小鼠的 GK、PPP 通量和 TG 积累的这些“矛盾”反应表明葡萄糖/葡萄糖-6-P 循环和 PPP 通量的调节，对于葡萄糖稳态很重要。我们认为并将证明 PPP 通量是 mTOR/Akt/AMPK 信号传导代谢物反馈控制中的重要环节。已知胰岛素刺激的 PI3-K/Akt 活性可通过磷酸化和易位至核 Foxol、FoxA2 和 GK 的细胞质来抑制 HGP、p-氧化和 TG 分泌。糖酵解通量诱导和脂肪酸 (FA) 合成取决于 SREBP-1c 和 ChREBP 的核转位。 SREBP-1c 和 ChREBP 协同诱导脂肪生成酶的表达，ChREBP 的激活取决于 PPP 中生成的木酮糖-5-P (X5P) 的量。 PPP 中产生的 NADPH 对于脂肪酸和 TG 合成至关重要，并且可以推测对胰岛素信号传导的额外代谢物反馈是由 TG 合成过程中产生的磷脂酸和二酰甘油产生的。此项资助的目的是了解 Pten 如何影响 Akt、AMPK 和 mTOR 之间的信号反馈，这些信号如何在禁食和进食状态下调节转录因子激活/易位，以及最后，这些禁食/进食信号事件如何依赖于体内-来自肝脏 PPP 和糖酵解/TG 合成途径的器官代谢物反馈，以及器官间通量调节机制。