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
• 负责人: Irwin Jack Kurland
• 金额: $ 10万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-12 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8064060
• 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

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（由申请方提供）：肝胰岛素作用：戊糖循环的作用。胰岛素在与其肝受体结合后，通过PI 3-K/Akt活化和随后的mTOR活化启动信号传导效应链的活化，刺激糖酵解、脂肪生成，并通过mTOR、葡萄糖-6-P脱氢酶（G6 PDH）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定的戊糖循环活性不仅仅是对PI 3-K/mTOR激活的被动反应。在全身Pten异源缺陷小鼠中，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通量再循环在禁食至进食过渡中不增加，基础肝葡萄糖产生不变，并且不发生肝甘油三酯（TG）的过度积累。这与肝脏特异性Pten KO相反，其特征在于基础低血糖和肝脏脂肪变性。GK表达被认为是肝脏PI 3-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是重要的。我们主张，并将表明PPP流量是mTOR/Akt/AMPK信号转导的代谢物反馈控制中的重要环节。已知胰岛素刺激的PI 3-K/Akt活性通过磷酸化和易位至核Foxol和FoxA 2以及GK的细胞质来抑制HGP、β-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的核转位。SREBP-1c和ChREBP协同诱导脂肪生成酶的表达，并且ChREBP的活化依赖于PPP中产生的木酮糖-5-P（X5 P）的量。PPP中产生的NADPH对脂肪酸和TG合成至关重要，并且可以假定对胰岛素信号传导的额外代谢物反馈是由TG合成期间产生的磷脂酸和二酰基甘油引起的。本研究旨在了解Pten如何影响Akt、AMPK和mTOR之间的信号反馈，这些信号如何调节空腹和进食状态下的转录因子激活/易位，以及这些空腹/进食信号事件如何依赖于来自肝脏PPP和糖酵解/TG合成途径的器官内代谢物反馈，以及器官间流量调节机制。