Regulation of Carbohydrate Metabolism and Lipogenesis

碳水化合物代谢和脂肪生成的调节

基本信息

  • 批准号:
    8621976
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-10-01 至 2016-09-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Abstract Evolutionary pressure has favored mechanisms that allow the body to efficiently store nutrients as fat when food is abundant as a safeguard against occasional famine. With the dramatic changes in modern lifestyle including consumption of high carbohydrate and high fat foods, these mechanisms may now be contributing to a major epidemic of obesity in the US where the majority of the population is overweight. Glucose is not only a major fuel of all mammalian tissues but also a source of carbon for fat and protein synthesis. The liver is the principal organ responsible for the conversion of excess dietary carbohydrate into triglycerides. Ingestion of a high carbohydrate diet induces transcription of more than 20 genes involved in the conversion of glucose to storage fat. A transcription factor with specificity for carbohydrate responsive elements (ChRE) found in the promoters of multiple genes required for lipogenesis and which displayed appropriate dietary responsive regulation, was first identified in my laboratory following purification from rat liver and termed "carbohydrate response element binding protein, ChREBP". The complete process by which ChREBP is activated in response to excess carbohydrate in order to induce the transcription of lipogenesis enzyme genes and then is turned off is not yet fully understood. We have shown that glucose and cAMP have antagonistic roles in the regulation of ChREBP activities in part through phosphorylation and dephosphorylation of multiple sites on ChREBP. Glucose stimulates dephosphorylation of at least some of these sites by activating a Xu5P-stimulated protein phosphatase, Xu5P-PP2A. More recently we have found that the interaction of ChREBP with 14-3-3 is one of the most important steps in regulation of the nuclear localization of ChREBP. The phosphorylation of ChREBP enhances the binding to 14-3-3 and is essential for export of ChREBP out of the nucleus under fasting conditions. In addition, we found that certain metabolites in fasted liver, but not in fed liver, promote the interaction of ChREBP with 14-3-3, and thereby export of ChREBP out of the nucleus. We have identified the metabolites as ketone bodies. To characterize the metabolites further we propose to (1) determine the biochemical mechanism by which they promote the interaction between ChREBP and 14-3-3, (2) determine their physiological significance in inhibition of ChREBP activities in hepatocytes, and (3) investigate whether the metabolites are signaling compounds for regulation of the subcellular localization of ChREBP in response to nutrients and fasting in vivo. We also will investigate other glucose signaling compounds in high sucrose fed rat liver extracts that may increase importin ¿ binding and/or destabilize 14-3-3 binding to promote the nuclear import of ChREBP. X-ray crystallography will be used to investigate the mechanisms of metabolite regulation of ChREBP binding to 14-3-3 and importin ¿ at an atomic level.
描述(由申请人提供): 摘要进化压力有利于这样的机制,即当食物充足时,身体可以有效地储存脂肪等营养物质,以防止偶尔发生的饥荒。随着现代生活方式的戏剧性变化,包括高碳水化合物和高脂肪食物的消费,这些机制现在可能会导致美国肥胖的主要流行,因为美国大多数人都超重。葡萄糖不仅是所有哺乳动物组织的主要燃料,也是脂肪和蛋白质合成的碳源。肝脏是负责将过量的饮食碳水化合物转化为甘油三酯的主要器官。摄入高碳水化合物饮食会诱导20多个基因转录,这些基因参与了将葡萄糖转化为储存脂肪的过程。在脂肪合成所需的多个基因的启动子中发现了一种对碳水化合物反应元件(CHRE)具有特异性的转录因子,该转录因子具有适当的饮食反应调节作用,在我的实验室从大鼠肝脏中纯化后首次发现,命名为“碳水化合物反应元件结合蛋白”。ChREBP被激活以响应过量碳水化合物以诱导脂肪生成酶基因转录,然后被关闭的完整过程尚未完全了解。我们已经证明,葡萄糖和cAMP在调节ChREBP活性方面有拮抗作用,部分是通过ChREBP上多个位点的磷酸化和去磷酸化。葡萄糖通过激活X5P刺激的蛋白磷酸酶X5P-PP2A来刺激至少其中一些位点的去磷酸化。最近我们发现,ChREBP与14-3-3的相互作用是调控ChREBP核定位的重要步骤之一。ChREBP的磷酸化增强了与14-3-3的结合,是禁食条件下ChREBP输出到细胞核外所必需的。此外,我们还发现,禁食肝脏中的某些代谢产物促进了ChREBP与14-3-3的相互作用,从而将ChREBP输出到细胞核外。我们已经鉴定了这些代谢物为酮体。为了进一步确定代谢产物的性质,我们建议(1)确定它们促进ChREBP与14-3-3相互作用的生化机制,(2)确定它们在抑制肝细胞ChREBP活性方面的生理意义,以及(3)研究这些代谢产物是否是调节ChREBP在体内对营养和禁食反应的亚细胞定位的信号化合物。我们还将研究高蔗糖喂养的大鼠肝脏提取物中的其他葡萄糖信号化合物,这些化合物可能会增加进口蛋白的结合和/或破坏14-3-3结合的稳定性,以促进ChREBP的核输入。X-射线结晶学将在原子水平上研究ChREBP与14-3-3和Importin结合的代谢物调节机制。

项目成果

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KOSAKU UYEDA其他文献

KOSAKU UYEDA的其他文献

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{{ truncateString('KOSAKU UYEDA', 18)}}的其他基金

Regulation of Carbohydrate Metabolism and Lipogenesis
碳水化合物代谢和脂肪生成的调节
  • 批准号:
    8762436
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
Regulation of Carbohydrate Metabolism and Lipogenesis
碳水化合物代谢和脂肪生成的调节
  • 批准号:
    8441895
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
MOLECULAR CONTROL OF GLUCOSE METABOLISM
葡萄糖代谢的分子控制
  • 批准号:
    7724102
  • 财政年份:
    2008
  • 资助金额:
    --
  • 项目类别:
MOLECULAR CONTROL OF GLUCOSE METABOLISM
葡萄糖代谢的分子控制
  • 批准号:
    7600836
  • 财政年份:
    2007
  • 资助金额:
    --
  • 项目类别:
MOLECULAR CONTROL OF GLUCOSE METABOLISM
葡萄糖代谢的分子控制
  • 批准号:
    7357881
  • 财政年份:
    2006
  • 资助金额:
    --
  • 项目类别:
MOLECULAR CONTROL OF GLUCOSE METABOLISM
葡萄糖代谢的分子控制
  • 批准号:
    7180717
  • 财政年份:
    2005
  • 资助金额:
    --
  • 项目类别:
Carbohydrate Regulation of Hepatic Gene Expression
碳水化合物对肝基因表达的调节
  • 批准号:
    6837591
  • 财政年份:
    2004
  • 资助金额:
    --
  • 项目类别:
Carbohydrate Regulation of Hepatic Gene Expression
碳水化合物对肝基因表达的调节
  • 批准号:
    6984777
  • 财政年份:
    2004
  • 资助金额:
    --
  • 项目类别:
Carbohydrate Regulation of Hepatic Gene Expression
碳水化合物对肝基因表达的调节
  • 批准号:
    7787585
  • 财政年份:
    2004
  • 资助金额:
    --
  • 项目类别:
Carbohydrate Regulation of Hepatic Gene Expression
碳水化合物对肝基因表达的调节
  • 批准号:
    6726531
  • 财政年份:
    2004
  • 资助金额:
    --
  • 项目类别:

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