Carbohydrate Regulation of Hepatic Gene Expression

碳水化合物对肝基因表达的调节

基本信息

  • 批准号:
    6837591
  • 负责人:
  • 金额:
    $ 26.65万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2004
  • 资助国家:
    美国
  • 起止时间:
    2004-01-01 至 2007-12-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Evolutional pressure has favored the ability to efficiently store nutrients as fat during abundant food supply as a safeguard against occasional famine. Due to the abundance of the food supply and dramatic changes in modern lifestyle, these genes may now contribute to major epidemic of obesity, especially in the US where over a half of population is overweight. This is predicted to be a major public health problem in the near future. The liver is the principal organ responsible for the conversion of excess dietary carbohydrate into triglycerides. Ingestion of high carbohydrate diet induces transcription of more than 15 genes involved in the metabolic conversion of glucose to storage fat. Until recently, it was thought that insulin and glucagons regulate the transcription of these genes. However, it has been shown that nutrients themselves play an important role in the regulation of transcription independent of insulin. The mechanism by which excess carbohydrate generates a signal to induce the transcription of lipogenesis enzyme gene is not known. We have identified and characterized a new transcription factor termed "Carbohydrate response element binding protein, ChREBP" which responds to high glucose and induce the liver pyruvate kinase (LPK) gene and lipogenic genes. Our goal is to understand how excess glucose, independent of insulin, activates the transcription. We have shown that glucose and cAMP are adversary in the lipognesis, cAMP and AMP inhibit ChREBP by phosphorylation at the specific sites which are mediated by protein kinase A and AMPprotein kinase. Glucose reverses the inhibition and activates ChREBP to favor triglycerides synthesis. We propose that glucose activates the transcription of these genes by dephosphorylation catalyzed by a specific protein phosphatase that is activated by a glucose-signaling compound. Our specific objectives for the current application are: (1) identify the specific protein phosphatases (PPase) in cytosol and in nucleus that are responsible for the nuclear import and the DNA binding activity of ChREBP. (2) Detect and identify a glucose signaling compound which activates the PPases and the transcription. (3) Investigate the mechanism of import and export of ChREBP. The important question is whether the import and export of ChREBP are regulated only by phosphorylation and dephosphorylation. Determine the genes altered by the ChREBP gene knockout and characterize the resulting physiological and biochemical changes in these mice in order to understand the roles of ChREBP in vivo. Produce other crosses with ChREBP-/- such as ob/ob mice by breeding our knockout mice with the ob/ob animals for potential elimination of obesity. Other possibility is to produce a combination of ChREBP-/- and SREBP-/- that inhibit the major portion of lipogenesis in liver.
描述(由申请人提供):进化压力倾向于在充足的食物供应期间有效地将营养物质储存为脂肪,以防止偶尔的饥荒。由于食物供应的丰富和现代生活方式的巨大变化,这些基因现在可能是肥胖流行的主要原因,特别是在超过一半人口超重的美国。预计在不久的将来,这将成为一个主要的公共卫生问题。肝脏是负责将过量的膳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可诱导超过15个基因的转录,这些基因参与葡萄糖到储存脂肪的代谢转化。直到最近,人们还认为胰岛素和胰高血糖素调节这些基因的转录。然而,已有研究表明,营养物质本身在独立于胰岛素的转录调节中起着重要作用。过量碳水化合物产生信号诱导脂肪生成酶基因转录的机制尚不清楚。

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:
    $ 26.65万
  • 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:
    $ 26.65万
  • 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:
    8621976
  • 财政年份:
    2012
  • 资助金额:
    $ 26.65万
  • 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:
    $ 26.65万
  • 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:
    $ 26.65万
  • 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:
    $ 26.65万
  • 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:
    $ 26.65万
  • 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:
    $ 26.65万
  • 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:
    $ 26.65万
  • 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:
    $ 26.65万
  • 项目类别:

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  • 批准号:
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  • 财政年份:
    1997
  • 资助金额:
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  • 项目类别:
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