Adipose Triglyceride Lipase (ATGL) in Lipotoxicity and The Metabolic Syndrome

脂肪甘油三酯脂肪酶 (ATGL) 在脂毒性和代谢综合征中的作用

• 批准号: 8445405
• 负责人: ERIN E. KERSHAW
• 金额: $ 31.7万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445405
• 关键词: 1,2-diacylglycerol; Adipocytes; Adipose tissue; Animal Model; Biological Models; Cardiomyopathies; Cardiovascular Diseases; Ceramides; Choristoma; Data; Diabetes Mellitus; Diet; Diglycerides; Disease; Enzymes; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Functional disorder; Genetically Engineered Mouse; Glucose; Homeostasis; Human; Hydrolysis; In Vitro; Individual; Inflammation; Insulin; Insulin Resistance; Lipase; Lipids; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Modeling; Molecular; Mus; Muscle; Myopathy; Obesity; Outcome; Pathogenesis; Pathway interactions; Phenotype; Physiological; Process; Production; Relative (related person); Research Personnel; Role; Skeletal Muscle; Staging; Testing; Therapeutic; Tissues; Training; Transgenic Organisms; Triglycerides; blood glucose regulation; cell type; endoplasmic reticulum stress; genetic manipulation; global health; glucose metabolism; glucose tolerance; improved; in vivo; insight; insulin sensitivity; lipid metabolism; mitochondrial dysfunction; obesity treatment; overexpression; public health relevance; therapy design

DESCRIPTION (provided by applicant): Obesity and the metabolic syndrome are global health threats. Intracellular triacylglycerol (TG) accumulation is strongly associated with insulin resistance and metabolic complications of obesity. However, the mechanisms underlying TG accumulation and its relationship to lipid-induced toxic metabolic effects ("lipotoxicity") remain unclear. Emerging evidence suggests that non-TG lipid metabolites (i.e. diacylglycerols, ceramides, fatty-acyl CoAs, etc.) rather than TGs themselves are pathogenic for these disorders, indicating that interventions designed to enhance TG storage and/or reduce production of "toxic" lipid metabolites may protect against insulin resistance and lipotoxic metabolic disease. Adipose triglyceride lipase (ATGL) has recently been identified as the rate-limiting enzyme mediating TG hydrolysis, and is therefore a critical determinant of storage/production of toxic as well as essential lipid metabolites. Nevertheless, the role of ATGL in these processes, particularly in non-adipose tissues where ATGL is also expressed, remains poorly understood. Our preliminary data suggest that i) ATGL is expressed, highly regulated, and functionally relevant in adipose and non-adipose tissues, and ii) modulation of ATGL-mediated TG hydrolysis influences glucose homeostasis/ insulin action in vitro and in vivo in a tissue/cell type-specific manner. Understanding the relative contribution of ATGL in individual tissues to overall metabolic homeostasis in vivo as well as the mechanisms by which ATGL exerts these effects are essential for determining whether TG metabolism can be therapeutically modulated to protect against lipotoxic metabolic disease. The CENTRAL AIM of this proposal is to determine the tissue- specific contribution of ATGL-mediated TG hydrolysis in metabolically relevant tissues (adipose tissue and skeletal muscle) to lipotoxicity and the metabolic syndrome in vivo using genetically-engineered mice as model systems. Our OVERALL HYPOTHESIS is that dysregulation of ATGL-mediated TG hydrolysis, by modulating intracellular lipid homeostasis, is a major determinant of both tissue-specific and systemic glucose homeostasis/insulin action. To test this hypothesis, we will evaluate local and systemic lipid homeostasis and glucose homeostasis/insulin action in mice with tissue-specific modulation of ATGL in adipose tissue (AIM 1) and skeletal muscle (AIM 2). We will further define the molecular mechanisms by which modulation of ATGL alters lipid homeostasis and glucose homeostasis/insulin action by evaluating specific mechanisms that contribute to lipotoxicity (i.e. endoplasmic reticulum stress, mitochondrial dysfunction, inflammation, etc.). These studies will promote the understanding of ATGL in tissue-specific and systemic metabolism, thereby providing important insights into the pathogenesis and treatment of obesity and related metabolic disorders. This is the first R01 application of an early stage investigator.

描述（由申请人提供）：肥胖和代谢综合征是全球健康威胁。细胞内三酰甘油（TG）积累与胰岛素抵抗和肥胖代谢并发症密切相关。然而，TG 积累的机制及其与脂质诱导的毒性代谢效应（“脂毒性”）的关系仍不清楚。新出现的证据表明，非 TG 脂质代谢物（即二酰基甘油、神经酰胺、脂肪酰基 CoA 等）而不是 TG 本身对这些疾病具有致病性，这表明旨在增强 TG 储存和/或减少“有毒”物质产生的干预措施脂质代谢物可以预防胰岛素抵抗和脂毒性代谢疾病。脂肪甘油三酯脂肪酶 (ATGL) 最近被确定为介导 TG 水解的限速酶，因此是有毒和必需脂质代谢物储存/生产的关键决定因素。然而，ATGL 在这些过程中的作用，特别是在 ATGL 也表达的非脂肪组织中，仍然知之甚少。我们的初步数据表明，i) ATGL 在脂肪和非脂肪组织中表达、高度调节且功能相关，并且 ii) ATGL 介导的 TG 水解的调节影响组织/体内体外和体内的葡萄糖稳态/胰岛素作用。细胞类型特异性方式。了解 ATGL 在个体组织中对体内整体代谢稳态的相对贡献以及 ATGL 发挥这些作用的机制对于确定是否可以通过治疗性调节 TG 代谢来预防脂毒性代谢疾病至关重要。该提案的中心目标是使用基因工程小鼠作为模型系统，确定代谢相关组织（脂肪组织和骨骼肌）中 ATGL 介导的 TG 水解对体内脂毒性和代谢综合征的组织特异性贡献。我们的总体假设是，通过调节细胞内脂质稳态，ATGL 介导的 TG 水解失调是组织特异性和全身葡萄糖稳态/胰岛素作用的主要决定因素。为了检验这一假设，我们将评估脂肪组织 (AIM 1) 和骨骼肌 (AIM 2) 中 ATGL 的组织特异性调节小鼠的局部和全身脂质稳态和葡萄糖稳态/胰岛素作用。我们将通过评估导致脂毒性的具体机制（即内质网应激、线粒体功能障碍、炎症等），进一步定义 ATGL 调节改变脂质稳态和葡萄糖稳态/胰岛素作用的分子机制。这些研究将促进对 ATGL 在组织特异性和全身代谢中的理解，从而为肥胖和相关代谢紊乱的发病机制和治疗提供重要见解。这是早期研究者的第一个 R01 申请。