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
• 负责人: YUGUANG SHI
• 金额: $ 31.02万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/7657500
• 关键词: ATP Synthesis Pathway; Acyl Coenzyme A; Acyltransferase; Aging; Cardiac Myocytes; Cardiolipins; Cardiovascular Diseases; Cell Line; Cells; Cholesterol; Data; Defect; Development; Diabetes Mellitus; Diet; Drug Delivery Systems; Drug Industry; Enzymes; Fatty acid glycerol esters; Genes; Goals; Heart; Homeostasis; Hyperthyroidism; Insulin Receptor; Insulin Resistance; Knockout Mice; Link; Linoleic Acids; Lipids; Liver; Location; Mammalian Cell; Mediating; Membrane; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Modeling; Molecular; Mus; Muscle Cells; Obesity; Oxidative Phosphorylation; Oxidative Stress; Phospholipase; Phospholipid Metabolism; Phospholipids; Physiological; Play; Polyunsaturated Fatty Acids; Process; Production; Reactive Oxygen Species; Receptor Mediated Signal Transduction; Regulation; Research; Respiratory Chain; Respiratory physiology; Role; Side; Signal Transduction Pathway; Site; Skeletal Muscle; Testing; Transgenic Organisms; Work; base; deacylation; feeding; glucose uptake; in vivo; interest; mRNA Expression; mitochondrial dysfunction; novel; overexpression; oxidation; pi bond; prevent; public health relevance; response; stable cell line

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（由申请人提供）：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引起的代谢疾病发生的分子机制。 CL 是线粒体氧化磷酸化和 ATP 合成所需的关键线粒体磷脂。与胆固醇一样，CL也有“好”和“坏”之分，这是由亚油酸的含量决定的。好的 CL 的侧链以亚油酸为主，而坏的 CL 则富含长链多不饱和脂肪酸。好与坏 CL 的比例由“重塑”过程调节，该过程涉及磷脂酶的脱酰化和溶心磷脂酰基转移酶的再酰化。对活性氧 (ROS) 的反应有缺陷的 CL 重塑会导致不良 CL 的积累和线粒体功能障碍，这些功能最近被确定为代谢疾病（包括糖尿病、肥胖、心血管疾病和衰老）的常见缺陷。我们最近克隆了第一个参与缺陷 CL 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 ROS 响应的胰岛素抵抗中发挥着致病作用。该项目正在测试这样的假设：ALCAT1 响应氧化应激而产生的 CL 重塑缺陷会导致线粒体功能障碍，并加剧饮食引起的肥胖的代谢并发症。该提案将通过三个目标来实现：1）识别C2C12或L6稳定细胞系中ALCAT1过度表达引起的线粒体功能障碍和胰岛素抵抗的分子缺陷； 2) 评估小鼠ALCAT1缺陷对饮食引起的肥胖相关代谢并发症的生理影响； 3) 确定 ALCAT1 在 CL 重塑和磷脂代谢中的调节作用。目前的工作结果预计将填补氧化应激引起的线粒体功能障碍与肥胖相关代谢并发症发生之间缺失的联系。拟议的工作还将有助于验证 ALCAT1 作为糖尿病和肥胖症的新药物靶点，从而激发制药行业对开发代谢疾病新疗法的兴趣。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（例如糖尿病和心血管疾病）的根本原因。预计这项研究的结果将提供关键信息，说明抑制参与不良脂质合成的关键酶是否可以为糖尿病、肥胖症和心血管疾病提供新的治疗方法。