Role of acetyl-CoA metabolism in the response to dietary and thermal stress

乙酰辅酶A代谢在饮食和热应激反应中的作用

基本信息

  • 批准号:
    10909411
  • 负责人:
  • 金额:
    $ 26.31万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-12-06 至 2024-08-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Metabolic diseases including non-alcoholic fatty liver disease (NAFLD), type 2 diabetes, and cardiovascular disease, which are linked to obesity, pose a major threat to economic and healthcare systems worldwide. Accordingly, there is a great need for new therapeutic targets and strategies. Abnormal lipid metabolism, especially in the liver, is a hallmark of metabolic disease, and the enzyme ATP-citrate lyase (ACLY), which generates acetyl-CoA for lipid and cholesterol synthesis, has emerged as a promising therapeutic target against fatty liver. To this point, several ACLY inhibitors are in development for clinical use, and one that specifically targets hepatic ACLY has been FDA approved against high cholesterol. However, it is now appreciated that there are multiple routes to lipogenic acetyl-CoA that are tissue and diet dependent. For example, lipogenic acetyl-CoA can also be derived from acetate via acetyl-CoA synthetase 2 (ACSS2) in certain dietary contexts, and emerging data indicates additional pathways to lipogenic acetyl-CoA likely exist. Moreover, work in the last decade has conclusively shown that lipid homeostasis in humans requires coordination between the body’s thermal regulatory organs (brown adipose tissue) and its energy storing and distribution centers (the liver and white adipose tissue), which is corroborated by studies in murine models further indicating that brown fat and liver and the two most lipogenic organs. The implications of these discoveries are that targeting ACLY systemically in one tissue or dietary context may be beneficial while targeting it in another may be detrimental. Indeed, our published and preliminary data supported by this grant show there is considerable interplay between the ACLY and ACSS2 pathways in brown and white adipose tissues and liver that is both context (i.e. diet and temperature) dependent and compensatory. Thus, effectively deploying ACLY or ACSS2 inhibitors will require a much deeper understanding of the tissue, diet, and thermoregulatory dependent mechanisms by which lipogenic acetyl-CoA is synthesized and utilized in vivo. In this proposal, we leverage tools and techniques generated in the previous funding period to investigate the biological functions of ACLY and ACSS2 in thermogenic adipocytes (Aim 1) and hepatocytes (Aim 2). Our approach utilizes tissue-specific single and double knockout models of ACLY and ACSS2 that we have generated, and techniques in metabolomics, compartmentalized metabolite analysis, and in vivo stable isotope tracing that we have adapted for studying adipose tissues and liver. This work will be facilitated by a team of researchers with complementary expertise and who have collaborated productively for several years. Our long- term goal is to identify optimal strategies, such as drug/diet combination therapies, to help patients suffering from metabolic diseases.
项目总结

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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David A Guertin其他文献

A new era of understanding emin vivo/em metabolic flux in thermogenic adipocytes
生热脂肪细胞中理解 emin vivo/em 代谢通量的新时代
  • DOI:
    10.1016/j.gde.2023.102112
  • 发表时间:
    2023-12-01
  • 期刊:
  • 影响因子:
    3.600
  • 作者:
    John A Haley;Cholsoon Jang;David A Guertin
  • 通讯作者:
    David A Guertin

David A Guertin的其他文献

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{{ truncateString('David A Guertin', 18)}}的其他基金

Quantitative and functional analysis of brown fat nutrient fluxes in vivo and its role in organ metabolite exchange
体内棕色脂肪营养通量的定量和功能分析及其在器官代谢物交换中的作用
  • 批准号:
    10624850
  • 财政年份:
    2021
  • 资助金额:
    $ 26.31万
  • 项目类别:
Quantitative and functional analysis of brown fat nutrient fluxes in vivo and its role in organ metabolite exchange
体内棕色脂肪营养通量的定量和功能分析及其在器官代谢物交换中的作用
  • 批准号:
    10316282
  • 财政年份:
    2021
  • 资助金额:
    $ 26.31万
  • 项目类别:
Quantitative and functional analysis of brown fat nutrient fluxes in vivo and its role in organ metabolite exchange
体内棕色脂肪营养通量的定量和功能分析及其在器官代谢物交换中的作用
  • 批准号:
    10461885
  • 财政年份:
    2021
  • 资助金额:
    $ 26.31万
  • 项目类别:
Acetyl-CoA metabolism and nutrient sensing in adipocytes
脂肪细胞中的乙酰辅酶A代谢和营养感应
  • 批准号:
    10304153
  • 财政年份:
    2018
  • 资助金额:
    $ 26.31万
  • 项目类别:
Mechanistic Target of Rapamycin Pathways in Metabolism and Energy Expenditure
雷帕霉素代谢和能量消耗途径的机制目标
  • 批准号:
    10615070
  • 财政年份:
    2013
  • 资助金额:
    $ 26.31万
  • 项目类别:
Mechanistic Target of Rapamycin Pathways in Metabolism and Energy Expenditure
雷帕霉素代谢和能量消耗途径的机制目标
  • 批准号:
    10398039
  • 财政年份:
    2013
  • 资助金额:
    $ 26.31万
  • 项目类别:
Mechanistic Target of Rapamycin Pathways in Metabolism and Energy Expenditure
雷帕霉素代谢和能量消耗途径的机制目标
  • 批准号:
    8575320
  • 财政年份:
    2013
  • 资助金额:
    $ 26.31万
  • 项目类别:
Mechanistic Target of Rapamycin Pathways in Metabolism and Energy Expenditure
雷帕霉素代谢和能量消耗途径的机制目标
  • 批准号:
    8695338
  • 财政年份:
    2013
  • 资助金额:
    $ 26.31万
  • 项目类别:
Mechanistic Target of Rapamycin Pathways in Metabolism and Energy Expenditure
雷帕霉素代谢和能量消耗途径的机制目标
  • 批准号:
    8881160
  • 财政年份:
    2013
  • 资助金额:
    $ 26.31万
  • 项目类别:
Mechanistic Target of Rapamycin Pathways in Metabolism and Energy Expenditure
雷帕霉素代谢和能量消耗途径的机制目标
  • 批准号:
    9904610
  • 财政年份:
    2013
  • 资助金额:
    $ 26.31万
  • 项目类别:
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