Hepatic Insuling Action: Role of the Pentose Cycle

描述（由申请人提供）：肝脏胰岛素作用：戊糖循环的作用。胰岛素与肝脏受体结合后，通过PI3-K/Akt激活和随后的mTOR激活，启动信号效应链的激活，刺激糖酵解、脂肪生成，并通过mTOR刺激葡萄糖-6- p脱氢酶（G6PDH）和戊糖磷酸途径（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异质缺陷小鼠中，基础葡萄糖和胰岛素不变，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，在禁食到进食的转变中没有增加，基础肝脏葡萄糖生成不变，肝脏甘油三酯（tg）没有过量积累。这与肝脏特异性Pten KO相反，Pten KO的特征是基础低血糖和肝脏脂肪变性。GK表达被认为是肝脏PI3-K作用的一个指标，因此Pten小鼠对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信号代谢反馈控制的重要环节。已知胰岛素刺激的PI3-K/Akt活性通过磷酸化和转运到核Foxol、FoxA2和GK的细胞质中来抑制HGP、p-氧化和TG分泌。糖酵解通量诱导和脂肪酸（FA）合成依赖于SREBP-1c和ChREBP的核易位。SREBP-1c和ChREBP协同诱导脂肪生成酶表达，ChREBP的激活依赖于PPP中生成的木醛糖-5- p （X5P）的量。在PPP中产生的NADPH对于脂肪酸和TG的合成至关重要，并且可以假设在TG合成过程中产生的磷脂酸和二酰基甘油会产生额外的代谢产物反馈到胰岛素信号。该资助的目的是了解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的激活/易位，最后，这些禁食/进食信号事件如何依赖于肝脏PPP和糖酵解/TG合成途径的器官内代谢物反馈，以及器官间通量调节机制。

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.