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: 8214539
• 负责人: ERIN E. KERSHAW
• 金额: $ 32.85万
• 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/8214539
• 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. PUBLIC HEALTH RELEVANCE: Accumulation of fat in adipose and non-adipose tissues (i.e. muscle) is associated with complications of obesity including diabetes and cardiovascular disease. Adipose triglyceride lipase (ATGL) is a newly identified enzyme that breaks down fat, but the contribution of fat breakdown by this enzyme in specific individual tissues to whole body metabolism is not known. Understanding the physiological relevance and mechanistic underpinnings of tissue-specific ATGL-mediated fat breakdown will provide important insights into the pathophysiology and treatment of obesity and related metabolic disorders.

描述（由申请人提供）：肥胖和代谢综合征是全球健康威胁。细胞内三酰基甘油（TG）的积累与肥胖的胰岛素抵抗和代谢并发症密切相关。但是，TG积累的基础机制及其与脂质诱导的毒性代谢作用（“脂毒性”）的关系尚不清楚。新兴的证据表明，非TG脂质代谢产物（即二酰基甘油，神经酰胺，脂肪囊肿COAS等）而不是TGS本身对于这些疾病而言是致病性的，这表明旨在增强TG储存和/或减少“有毒毒性”的脂肪代谢和下替代疾病的干预措施可保护和降低“有毒”的产生。脂肪甘油三酸酯脂肪酶（ATGL）最近被确定为限制速率的酶介导TG水解，因此是毒性和必需脂质代谢物的储存/产生的关键决定因素。然而，ATGL在这些过程中的作用，尤其是在也表达ATGL的非注射液组织中，仍然对其进行了鲜明的了解。我们的初步数据表明，i）ATGL表达，高度调节并在功能上与脂肪和非脂肪组织相关，ii）调节ATGL介导的TG水解影响葡萄糖稳态/胰岛素稳态/胰岛素稳定蛋白在体外和体内的细胞/细胞类型类型方式。了解单个组织中ATGL对体内总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TG代谢是否可以在治疗上进行治疗以防止脂肪毒性代谢疾病。该提案的核心目的是确定ATGL介导的TG水解在代谢相关的组织（脂肪组织和骨骼肌）对脂肪毒性和使用基因工程小鼠作为模型系统的体内的组织（脂肪组织和骨骼肌）对代谢相关的组织的组织特异性贡献。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性葡萄糖稳态/胰岛素动作的主要决定因素。为了检验这一假设，我们将评估具有脂肪组织中ATGL组织特异性调节的小鼠中局部和全身性脂质稳态和葡萄糖稳态/胰岛素动作（AIM 1）和骨骼肌（AIM 2）。我们将进一步定义ATGL调节的分子机制，通过评估有助于脂肪毒性的特定机制来改变脂质稳态和葡萄糖稳态/胰岛素的作用（即内质网应激，线粒体功能障碍，炎症，等）。这些研究将促进对组织特异性和全身代谢中ATGL的理解，从而为肥胖症和相关代谢性疾病的发病机理和治疗提供重要见解。这是早期研究员的第一个R01应用。 公共卫生相关性：脂肪中脂肪的积累（肌肉）与肥胖并发症有关，包括糖尿病和心血管疾病。脂肪甘油三酸酯脂肪酶（ATGL）是一种新鉴定的酶，可分解脂肪，但是该酶在特定单个组织中的脂肪分解对整个身体代谢的贡献尚不清楚。了解组织特异性ATGL介导的脂肪分解的生理相关性和机理基础将为肥胖和相关代谢疾病的病理生理学和治疗提供重要的见解。