Regulation of Mitochondrial Dysfunction and Diet-Induced Obesity by ALCAT1

ALCAT1 对线粒体功能障碍和饮食引起的肥胖的调节

基本信息

  • 批准号:
    8080916
  • 负责人:
  • 金额:
    $ 30.4万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-07-15 至 2013-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The long term goal is to elucidate the molecular mechanisms by which defective cardiolipin (CL) metabolism contributes to the onset of mitochondrial dysfunction and metabolic diseases from oxidative stress. CL is a key mitochondrial phospholipid required for mitochondrial oxidative phosphorylation and ATP synthesis. Like cholesterols, there are "good" and "bad" CL, which is determined by the content of linoleic acid. The side chains of a good CL are dominated by linoleic acid, and a bad CL is enriched with long chain polyunsaturated fatty acids. The ratio of good vs. bad CL is modulated by a "remodeling" process that involves deacylation by phospholipases and reacylation by lysocardiolipin acyltransferases. Defective CL remodeling in response to reactive oxygen species (ROS) leads to accumulation of bad CL and mitochondrial dysfunction which have recently been identified as common defects in metabolic diseases including diabetes, obesity, cardiovascular diseases, and aging. We have recently cloned the first acyltransferase (ALCAT1) involved in defective CL remodeling. Our preliminary data demonstrate that ALCAT1 plays a causative role in mitochondrial dysfunction and insulin resistance in response to ROS. This project is test the hypothesis that defective CL remodeling by ALCAT1 in response to oxidative stress causes mitochondrial dysfunction and exacerbates metabolic complications in diet-induced obesity. The proposal will be accomplished by three Aims: 1) To identify molecular defects in mitochondrial dysfunction and insulin resistance caused by ALCAT1 overexpression in C2C12 or L6 stable cell lines; 2) To assess the physiological effects of ALCAT1 deficiency in mice on metabolic complications associated with diet-induced obesity; and 3) To determine the regulatory role of ALCAT1 in CL remodeling and phospholipid metabolism. Results from the current work are anticipated to fill in a missing link between mitochondrial dysfunction from oxidative stress and onset of metabolic complications associated with obesity. The proposed work will also help to validate ALCAT1 as a novel drug target for diabetes and obesity, and thereby stimulates pharmaceutical industry interests in development of novel treatment for metabolic diseases. PUBLIC HEALTH RELEVANCE: The proposed work will help to identify underlying causes of metabolic complications associated with obesity, such as diabetes and cardiovascular diseases. The results from the proposed research are anticipated to provide key information on whether inhibition of a key enzyme involved in synthesis of a bad lipid can provide a novel treatment of diabetes, obesity, and cardiovascular diseases.
描述(申请人提供):长期目标是阐明心磷脂(CL)代谢缺陷导致线粒体功能障碍和氧化应激所致代谢性疾病的分子机制。CL是线粒体氧化磷酸化和ATP合成所需的一种关键的线粒体磷脂。和胆固醇一样,CL也有“好”和“坏”之分,这是由亚油酸的含量决定的。好的CL的侧链主要是亚油酸,而坏的CL富含长链多不饱和脂肪酸。好的和坏的CL的比率是由一个“重塑”过程调节的,这个过程包括磷脂酶的脱酰化和溶心磷脂酰基转移酶的反应。活性氧(ROS)引起的CL重塑缺陷会导致不良CL的积聚和线粒体功能障碍,近年来发现这些缺陷是糖尿病、肥胖症、心血管疾病和衰老等代谢性疾病中常见的缺陷。我们最近克隆了第一个参与CL缺陷重塑的酰基转移酶(ALCAT1)。我们的初步数据表明,ALCAT1在线粒体功能障碍和胰岛素抵抗对ROS的反应中起着致病作用。本项目旨在验证ALCAT1对氧化应激反应中CL重塑缺陷导致线粒体功能障碍并加剧饮食诱导肥胖代谢并发症的假设。该提案将通过三个目标完成:1)确定在C2C12或L6稳定细胞系中ALCAT1过表达导致的线粒体功能障碍和胰岛素抵抗的分子缺陷;2)评估ALCAT1缺陷对小鼠饮食诱导肥胖相关代谢并发症的生理影响;以及3)确定ALCAT1在CL重塑和磷脂代谢中的调节作用。目前的工作结果有望填补氧化应激导致的线粒体功能障碍与肥胖相关的代谢并发症之间缺失的联系。这项拟议的工作还将有助于验证ALCAT1作为治疗糖尿病和肥胖症的新药靶点的有效性,从而激发制药行业开发新药治疗代谢性疾病的兴趣。公共卫生相关性:拟议的工作将有助于确定与肥胖相关的代谢并发症的潜在原因,如糖尿病和心血管疾病。这项拟议研究的结果有望提供关键信息,即抑制参与合成不良脂质的关键酶是否可以为糖尿病、肥胖和心血管疾病提供一种新的治疗方法。

项目成果

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YUGUANG SHI其他文献

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{{ truncateString('YUGUANG SHI', 18)}}的其他基金

Cellular mechanisms of NLRP3 activation by ALCAT1 in diet-induced obesity
饮食诱导肥胖中 ALCAT1 激活 NLRP3 的细胞机制
  • 批准号:
    10658507
  • 财政年份:
    2023
  • 资助金额:
    $ 30.4万
  • 项目类别:
Cardiolipin Remodeling in Alzheimer’s Disease
阿尔茨海默病中的心磷脂重塑
  • 批准号:
    10645569
  • 财政年份:
    2023
  • 资助金额:
    $ 30.4万
  • 项目类别:
Cellular Senescence in Aging-related Metabolic Diseases
衰老相关代谢疾病中的细胞衰老
  • 批准号:
    9904308
  • 财政年份:
    2017
  • 资助金额:
    $ 30.4万
  • 项目类别:
Cellular Senescence in Aging-related Metabolic Diseases
衰老相关代谢疾病中的细胞衰老
  • 批准号:
    9566816
  • 财政年份:
    2017
  • 资助金额:
    $ 30.4万
  • 项目类别:
Regulation of Mitochondrial Dysfunction in Diet-Induced Obesity by ALCAT-1
ALCAT-1 对饮食引起的肥胖中线粒体功能障碍的调节
  • 批准号:
    8996564
  • 财政年份:
    2015
  • 资助金额:
    $ 30.4万
  • 项目类别:
Regulation of Mitochondrial Dysfunction in Diet-Induced Obesity by ALCAT-1
ALCAT-1 对饮食引起的肥胖中线粒体功能障碍的调节
  • 批准号:
    9126692
  • 财政年份:
    2015
  • 资助金额:
    $ 30.4万
  • 项目类别:
Regulation of Mitochondrial Dysfunction in Diet-Induced Obesity by ALCAT-1
ALCAT-1 对饮食引起的肥胖中线粒体功能障碍的调节
  • 批准号:
    8804945
  • 财政年份:
    2008
  • 资助金额:
    $ 30.4万
  • 项目类别:
Regulation of Mitochondrial Dysfunction in Diet-Induced Obesity by ALCAT-1
ALCAT-1 对饮食引起的肥胖中线粒体功能障碍的调节
  • 批准号:
    8642488
  • 财政年份:
    2008
  • 资助金额:
    $ 30.4万
  • 项目类别:
Regulation of Mitochondrial Dysfunction and Diet-Induced Obesity by ALCAT1
ALCAT1 对线粒体功能障碍和饮食引起的肥胖的调节
  • 批准号:
    8288795
  • 财政年份:
    2008
  • 资助金额:
    $ 30.4万
  • 项目类别:
Regulation of Mitochondrial Dysfunction and Diet-Induced Obesity by ALCAT1
ALCAT1 对线粒体功能障碍和饮食引起的肥胖的调节
  • 批准号:
    7657500
  • 财政年份:
    2008
  • 资助金额:
    $ 30.4万
  • 项目类别:

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  • 批准号:
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  • 财政年份:
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  • 批准号:
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  • 财政年份:
    1996
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