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:
    7822745
  • 负责人:
  • 金额:
    $ 35.75万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-06-01 至 2012-04-30
  • 项目状态:
    已结题

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:五旬节周期的作用。胰岛素与其肝受体结合后,通过PI3-K/AKT激活引发信号效应链的激活,并随后激活MTOR激活,刺激糖酵解,脂肪生成,脂肪生成,MTOR,MTOR,葡萄糖-6-6-P脱氢酶(G6PDH)(G6PDH)和载液裂变(pppp)(Ppppppate)。我们的数据表明,使用稳定的同位素通量表型测量的五型循环活性不仅是对PI3-K/MTOR激活的被动反应。在整个体内PTEN异质不足的小鼠中,基础葡萄糖和胰岛素是不变的,葡萄糖酶(GK)在基础状态下被下调,PPP通量和葡萄糖/葡萄糖-6-P Reclux重新循环,在快速过渡的兴奋性glucation do not comgutation not(均未累积)中,并未增加(均未增加)没有发生。这与肝特异性PTEN KO相反,后者的特征是基底低血糖和肝脂肪变性。 GK表达被认为是肝PI3-K作用的指标,因此对于PTEN小鼠,这些对GK,PPP通量和TG积累的“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非常重要。我们认为,并将表明PPP通量是MTOR/AKT/AMPK信号的代谢物反馈控制中的重要链接。已知胰岛素刺激的PI3-K/AKT活性可通过磷酸化抑制HGP,P-氧化和TG分泌,并转移到核Foxol和FoxA2和GK的细胞质中。糖酵解通量诱导和脂肪酸(FA)合成取决于SREBP-1C和CHREBP的核转运。 SREBP-1C和CHREBP协同诱导脂肪酶表达,Chrebp的激活取决于PPP中产生的xylulose-5-P(X5P)的量。在PPP中产生的NADPH对于脂肪酸和TG合成至关重要,可以假设胰岛素信号传导的其他代谢物反馈是由TG合成过程中磷酸和二酰基甘油产生的。 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.

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Irwin Jack Kurland其他文献

Irwin Jack Kurland的其他文献

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{{ truncateString('Irwin Jack Kurland', 18)}}的其他基金

AB Sciex 6500+ QTRAP with Selexion for ultra-sensitive metabolomics and lipidomics
带 Selexion 的 AB Sciex 6500 QTRAP 用于超灵敏代谢组学和脂质组学
  • 批准号:
    9275202
  • 财政年份:
    2017
  • 资助金额:
    $ 35.75万
  • 项目类别:
AB Sciex 6500+ QTRAP with Selexion for ultra-sensitive metabolomics and lipidomics
带 Selexion 的 AB Sciex 6500 QTRAP 用于超灵敏代谢组学和脂质组学
  • 批准号:
    9864491
  • 财政年份:
    2017
  • 资助金额:
    $ 35.75万
  • 项目类别:
Stable Isotope & Metabolomics Core
稳定同位素
  • 批准号:
    8872950
  • 财政年份:
    2015
  • 资助金额:
    $ 35.75万
  • 项目类别:
Hepatic Insuling Action: Role of the Pentose Cycle
肝脏绝缘作用:戊糖循环的作用
  • 批准号:
    8064060
  • 财政年份:
    2010
  • 资助金额:
    $ 35.75万
  • 项目类别:
Stable Isotope and Metabolomics Core
稳定同位素和代谢组学核心
  • 批准号:
    7925426
  • 财政年份:
    2010
  • 资助金额:
    $ 35.75万
  • 项目类别:
Stable Isotope amd Metabolomics Core
稳定同位素和代谢组学核心
  • 批准号:
    8013183
  • 财政年份:
    2010
  • 资助金额:
    $ 35.75万
  • 项目类别:
Hepatic Insuling Action: Role of the Pentose Cycle
肝脏绝缘作用:戊糖循环的作用
  • 批准号:
    8016877
  • 财政年份:
    2009
  • 资助金额:
    $ 35.75万
  • 项目类别:
Hepatic Insuling Action: Role of the Pentose Cycle
肝脏绝缘作用:戊糖循环的作用
  • 批准号:
    8105053
  • 财政年份:
    2009
  • 资助金额:
    $ 35.75万
  • 项目类别:
EARLY DETECTION OF GESTATIONAL DIABETES BY METABOLOMICS AND PROTEOMICS
通过代谢组学和蛋白质组学早期检测妊娠糖尿病
  • 批准号:
    7607891
  • 财政年份:
    2007
  • 资助金额:
    $ 35.75万
  • 项目类别:
Hepatic Insulin Action: Role of the Pentose Cycle
肝胰岛素作用:戊糖循环的作用
  • 批准号:
    6708920
  • 财政年份:
    2002
  • 资助金额:
    $ 35.75万
  • 项目类别:

相似海外基金

Hepatic Insuling Action: Role of the Pentose Cycle
肝脏绝缘作用:戊糖循环的作用
  • 批准号:
    8064060
  • 财政年份:
    2010
  • 资助金额:
    $ 35.75万
  • 项目类别:
Hepatic Insuling Action: Role of the Pentose Cycle
肝脏绝缘作用:戊糖循环的作用
  • 批准号:
    8016877
  • 财政年份:
    2009
  • 资助金额:
    $ 35.75万
  • 项目类别:
Hepatic Insuling Action: Role of the Pentose Cycle
肝脏绝缘作用:戊糖循环的作用
  • 批准号:
    8105053
  • 财政年份:
    2009
  • 资助金额:
    $ 35.75万
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Hepatic Insuling Action: Role of the Pentose Cycle
肝脏绝缘作用:戊糖循环的作用
  • 批准号:
    7459073
  • 财政年份:
    2002
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Hepatic Insuling Action: Role of the Pentose Cycle
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