ROLE OF THE MONOACYLGLYCEROL ACYLTRANSFERASE PATHWAY IN ADIPOSE TISSUE TRIGLYCERIDE METABOLISM

单酰甘油酰基转移酶途径在脂肪组织甘油三酯代谢中的作用

• 批准号: 9517370
• 负责人: Angela Marie Hall
• 金额: $ 30.5万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-21 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9517370
• 关键词: 2-acylglycerol O-acyltransferase; Adipocytes; Adipose tissue; Affect; Anabolism; Automobile Driving; Belief; Biology; Blood Circulation; Buffers; Cardiovascular Diseases; Cardiovascular system; Cells; Coronary heart disease; Data; Dementia; Deposition; Development; Dietary Fats; Disease; Energy Metabolism; Enterocytes; Epidemic; Fasting; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Future; Gene Expression; High Fat Diet; Hypertension; Hypertriglyceridemia; Impairment; Individual; Inflammation; Intestines; Knowledge; Lipase; Lipids; Lipolysis; Liver diseases; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Minor; Molecular; Monoglycerides; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nutrient; Obesity; Obstructive Sleep Apnea; Pathway interactions; Play; Process; Product Recycling; Recycling; Regulation; Role; Stimulus; Stroke; Testing; Therapeutic; Time; Tissues; Treatment Efficacy; Triglyceride Metabolism; Triglycerides; Weight; Work; absorption; adipocyte differentiation; adipokines; alpha-glycerophosphoric acid; base; cancer type; cell type; design; effective therapy; fatty acid metabolism; global health; in vivo; inhibitor/antagonist; innovation; insight; knock-down; lipid metabolism; loss of function; novel; novel therapeutic intervention; obesity treatment; prevent; protein acyltransferase; uptake

ABSTRACT The number of obese individuals worldwide has reached epidemic proportions and is a major global health concern. Excessive adipose tissue stores predispose individuals to developing type 2 diabetes, hypertension, coronary heart disease, stroke, fatty liver disease, dementia, obstructive sleep apnea and many types of cancer. Adipose tissue acts as the master regulator of lipid storage, and through secretion of adipokines, influences many systemic processes, including energy metabolism, inflammation, and pathophysiological changes associated with disease. A more thorough understanding of the pathways that regulate triglyceride synthesis and storage is necessary for the development of new effective therapeutic treatments of obesity. There are two independent, but convergent pathways for triglyceride biosynthesis. The glycerol-3-phosphate (G3P) pathway or Kennedy pathway is considered the predominant pathway in most cell types. The alternative pathway for triglyceride biosynthesis, known as monoacylglycerol acyltransferase (MGAT) pathway has been most extensively characterized in intestinal enterocytes where it is involved in dietary fat absorption. This application is designed to test the novel and innovative hypotheses that the MGAT pathway of triglyceride synthesis is important for controlling lipid metabolism in adipose tissue and that perturbations in this pathway affect adipose tissue triglyceride synthesis and metabolism. We have postulated that MGAT activity facilitates incorporation of lipid into its preferred and inert storage form in adipocytes and prevents free fatty acids from entering circulation. The studies proposed herein are designed to: [1] define the role that MGAT activity plays in adipocyte triglyceride metabolism, [2] to examine the role of adipose tissue MGAT1 in states associated with increased lipolysis, and [3] to test the role MGAT1 in regulating adipocyte and whole body lipid metabolism by an in vivo loss-of-function approach. The results of these studies will not only have implications for our understanding of the biology of MGAT proteins, but will also provide new insight into the basic molecular regulation of monoacylglycerol and FFA metabolism in adipose tissue. More importantly, modulation of MGAT1 expression and activity in adipose tissue may represent a novel and effective treatment of obesity.

摘要 全世界肥胖者的数量已经达到流行病的比例，是全球主要的健康问题 担忧。过多的脂肪组织储存使人容易患上2型糖尿病、高血压、 冠心病、中风、脂肪肝、痴呆症、阻塞性睡眠呼吸暂停和许多类型的 癌症。脂肪组织作为脂肪储存的主要调节器，通过分泌脂肪因子， 影响许多全身过程，包括能量代谢、炎症和病理生理学。 与疾病相关的变化。对调节甘油三酯的途径有更深入的了解 合成和储存对于开发新的有效的肥胖症治疗方法是必要的。 甘油三酯的生物合成有两条独立但又趋同的途径。甘油-3-磷酸 在大多数细胞类型中，G3P途径或Kennedy途径被认为是最主要的途径。另一个选择 甘油三酯生物合成途径，称为单酰甘油酰基转移酶(MGAT)途径 最广泛的特点是在肠道细胞，在那里它参与饮食脂肪的吸收。这 应用程序旨在测试新的和创新的假设，甘油三酯的MGAT途径 合成对于控制脂肪组织中的脂肪代谢很重要，这一途径中的扰动 影响脂肪组织甘油三酯的合成和代谢。我们假设MGAT活动促进了 在脂肪细胞中将脂肪纳入其首选的和惰性的存储形式，并防止游离脂肪酸 进入流通领域。本文建议的研究旨在：[1]确定MGAT活动所起的作用 在脂肪细胞甘油三酯代谢中，[2]研究脂肪组织MGAT1在与 增加脂肪分解，以及[3]测试MGAT1在调节脂肪细胞和全身脂肪代谢中的作用 一种体内功能丧失的方法。这些研究的结果不仅对我们的 了解MGAT蛋白的生物学，但也将提供对基本分子的新见解 脂肪组织中单酰甘油和游离脂肪酸代谢的调节。更重要的是，MGAT1的调制 脂肪组织中的表达和活性可能代表着一种新的有效的肥胖治疗方法。