Coenzyme A Regulation of Metabolism

辅酶 A 代谢调节

基本信息

项目摘要

DESCRIPTION (provided by applicant): This proposal is an extension of an evolving program investigating the importance of pantothenate kinase (PanK) regulation of coenzyme A (CoA) biosynthesis to the control of intermediary metabolism. The accomplished aims of the last grant period defined the regulatory properties and tissue-specific distribution of the PanK isoforms, generated a knockout mouse model that was used to reveal the critical importance of increasing CoA levels in fasting metabolism, employed a chemical biology approach to identify small molecule PanK inhibitors, and identified acyl-carnitine as a PanK activator. These results have refined our overall idea that altering the intracellular CoA concentration is essential for reprogramming metabolism. In the past, intracellular CoA has been considered to be in excess of what is needed to fully support CoA-dependent biochemistry, with acetyl-CoA exerting feedback control over PanK activity to buffer the cellular CoA content. This view is not correct. Our results show that the CoA supply is dynamically regulated and the failure to modulate CoA content directly impacts fuel utilization by the metabolic network. This unappreciated aspect of regulation is central to understanding the nutritional reprogramming of intermediary metabolism. The experiments in Aim #1 will determine the role of adjusting CoA levels in the transition of muscle from fed to fasting metabolism. The results from this part of the study will be of central importance to understanding the dependence of energy generation in muscle on CoA content. In humans, there is an association between low serum insulin levels and polymorphisms in the PANK1 gene. Prominent phenotypes of our Pank1/ knockout mouse are lower serum glucose, triglycerides and insulin levels. In Aim #2, we will use our Pank1/ mouse model to define the underlying metabolic basis for reduced insulin levels and to determine if muscle is the primary site for increased glucose tolerance in these animals. CoA and its thioesters are concentration- dependent substrates and allosteric regulators of key control points in intermediary metabolism, suggesting that the pharmacological manipulation of CoA levels via PanK inhibition could reprogram metabolism. This idea was validated by our experiments with a PanK inhibitor that lowers hepatic CoA and serum glucose in mice. In Aim #3, we will use this inhibitor to reduce total CoA content to pharmacologically reprogram hepatic metabolism to suppress gluconeogenesis in diet-induced obesity, and determine if the elevation of hepatic CoA is sufficient to increase glucose production. This original approach to reprogramming intermediary metabolism will define the role of CoA in hepatic gluconeogenesis and provide insight into the factors that give rise to human disorders of lipid and glucose homeostasis. PUBLIC HEALTH RELEVANCE: Obesity-associated insulin resistance and hyperglycemia define a metabolic syndrome (type 2 diabetes) that constitutes a large and ever growing medical problem affecting the United States population. The need for more suitable therapeutics to treat this syndrome has focused considerable attention on clearly understanding the normal regulation of intermediary metabolism and the imbalances associated with metabolic syndrome. This research will define the role of pantothenate kinase and coenzyme A in the regulation of intermediary metabolism and its effect on glucose and insulin homeostasis.
描述(由申请人提供):该提案是一项不断发展的计划的延伸,该计划研究了泛酸激酶(PanK)对辅酶A(CoA)生物合成的调节对中间代谢控制的重要性。最后一个资助期完成的目标定义了PanK亚型的调节特性和组织特异性分布,产生了一个敲除小鼠模型,用于揭示增加CoA水平在空腹代谢中的至关重要性,采用化学生物学方法鉴定小分子PanK抑制剂,并鉴定酰基肉毒碱作为PanK激活剂。这些结果完善了我们的总体思路,即改变细胞内CoA浓度对于重编程代谢至关重要。在过去,细胞内CoA被认为超过了完全支持CoA依赖性生物化学所需的量,其中乙酰CoA对PanK活性施加反馈控制以缓冲细胞CoA含量。这种看法是不正确的。我们的研究结果表明,辅酶A的供应是动态调节和未能调节辅酶A含量直接影响燃料利用的代谢网络。这种未被重视的调节方面是理解中间代谢的营养重编程的核心。目标#1中的实验将确定在肌肉从进食到禁食代谢的转变中调节CoA水平的作用。这部分研究的结果对于了解肌肉中能量产生对CoA含量的依赖性至关重要。在人类中,低血清胰岛素水平与PANK 1基因多态性之间存在关联。我们的Pank 1/敲除小鼠的突出表型是较低的血清葡萄糖、甘油三酯和胰岛素水平。在目标#2中,我们将使用我们的Pank 1/小鼠模型来定义胰岛素水平降低的潜在代谢基础,并确定肌肉是否是这些动物中葡萄糖耐量增加的主要部位。CoA及其硫酯是中间代谢中关键控制点的浓度依赖性底物和变构调节剂,表明通过PanK抑制对CoA水平的药理学操纵可以重新编程代谢。我们用PanK抑制剂降低小鼠肝脏CoA和血清葡萄糖的实验证实了这一想法。在目标#3中,我们将使用这种抑制剂来降低总CoA含量,以重新编程肝脏代谢,从而抑制饮食诱导的肥胖症中的肝脏生成,并确定肝脏CoA的升高是否足以增加葡萄糖的产生。这种重新编程中间代谢的原始方法将定义CoA在肝细胞生成中的作用,并提供对引起人类脂质和葡萄糖稳态紊乱的因素的深入了解。 公共卫生相关性:肥胖相关的胰岛素抵抗和高血糖症定义了代谢综合征(2型糖尿病),其构成了影响美国人口的大的且不断增长的医学问题。需要更合适的治疗方法来治疗这种综合征集中了相当大的注意力,清楚地了解中间代谢的正常调节和与代谢综合征相关的失衡。本研究将明确泛酸激酶和辅酶A在中间代谢调节中的作用及其对葡萄糖和胰岛素稳态的影响。

项目成果

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SUZANNE JACKOWSKI其他文献

SUZANNE JACKOWSKI的其他文献

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{{ truncateString('SUZANNE JACKOWSKI', 18)}}的其他基金

Regulation of Coenzyme A Levels by Pantothenate Kinase
泛酸激酶对辅酶 A 水平的调节
  • 批准号:
    6904470
  • 财政年份:
    2002
  • 资助金额:
    $ 39.38万
  • 项目类别:
Regulation of Coenzyme A Levels by Pantothenate Kinase
泛酸激酶对辅酶 A 水平的调节
  • 批准号:
    6542402
  • 财政年份:
    2002
  • 资助金额:
    $ 39.38万
  • 项目类别:
Coenzyme A Regulation of Metabolism
辅酶 A 代谢调节
  • 批准号:
    8470174
  • 财政年份:
    2002
  • 资助金额:
    $ 39.38万
  • 项目类别:
Regulation of Coenzyme A Levels by Pantothenate Kinase
泛酸激酶对辅酶 A 水平的调节
  • 批准号:
    6640115
  • 财政年份:
    2002
  • 资助金额:
    $ 39.38万
  • 项目类别:
Regulation of Coenzyme A Levels by Pantothenate Kinase
泛酸激酶对辅酶 A 水平的调节
  • 批准号:
    6754431
  • 财政年份:
    2002
  • 资助金额:
    $ 39.38万
  • 项目类别:
Regulation of Coenzyme A Levels by Panothenate Kinase
泛酸激酶对辅酶 A 水平的调节
  • 批准号:
    7625078
  • 财政年份:
    2002
  • 资助金额:
    $ 39.38万
  • 项目类别:
Coenzyme A Regulation of Metabolism
辅酶 A 代谢调节
  • 批准号:
    8663281
  • 财政年份:
    2002
  • 资助金额:
    $ 39.38万
  • 项目类别:
Coenzyme A Regulation of Metabolism
辅酶 A 代谢调节
  • 批准号:
    8334463
  • 财政年份:
    2002
  • 资助金额:
    $ 39.38万
  • 项目类别:
Regulation of Coenzyme A Levels by Panothenate Kinase
泛酸激酶对辅酶 A 水平的调节
  • 批准号:
    7256677
  • 财政年份:
    2001
  • 资助金额:
    $ 39.38万
  • 项目类别:
REGULATION OF MEMBRANE PHOSPHOLIPID SYNTHESIS
膜磷脂合成的调控
  • 批准号:
    2835564
  • 财政年份:
    1991
  • 资助金额:
    $ 39.38万
  • 项目类别:

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钯催化的硅烷化乙酸烯丙酯新型有机转化的开发
  • 批准号:
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