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Adaptation to ceramide involves AKT/FOXO regulated novel triglyceride lipases

对神经酰胺的适应涉及 AKT/FOXO 调节的新型甘油三酯脂肪酶

基本信息

批准号：
9118308
负责人：
USHA R ACHARYA
金额：
$ 33.95万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9118308
关键词：
Acyl Coenzyme A Address Affect Animals Antibodies Cardiovascular Diseases Catabolism Ceramides Complex Complications of Diabetes Mellitus Data Defect Diabetes Mellitus Diet Disease Drosophila genus Energy Metabolism Energy-Generating Resources Enhancers Ensure Environment Failure Fat Body Fatty acid glycerol esters Genetic Glycolysis Goals Health Heart Heart Abnormalities Heart Diseases Homeostasis Human Hypertriglyceridemia Impairment Lipase Lipids Lipolysis Mediating Metabolic syndrome Metabolism Mitochondria Modeling Mus Myocardial dysfunction Non-Insulin-Dependent Diabetes Mellitus Obesity Organ Organism Outcome Pathway interactions Phenotype Physiological Process Production Proteins Proto-Oncogene Proteins c-akt RNA Interference Reagent Regulation Risk Factors Role Site Source Sphingolipids Starvation Stress Time Tissues Transgenic Organisms Triglyceride Metabolism Triglycerides carbohydrate metabolism diabetic energy balance fatty acid transport fly genetic approach human morbidity human mortality insight knock-down lipid metabolism mouse model mutant novel obesity risk overexpression prevent research study response stable cell line sugar tool

项目摘要

DESCRIPTION (provided by applicant): Triacylglycerols are a source of fatty acyl CoA and serve as stores of energy in organisms. They are mobilized during conditions of stress and high-energy activity for efficient energy production. Defects in mobilizing triacylglycerol results in several human disorders such as obesity, metabolic syndrome and is a complication of diabetes and cardiovascular disorders. The sphingolipid ceramide affects cellular energy metabolism by interfering with mitochondrial function. In a Drosophila model that accumulates ceramide, we investigated how it adapts to compromised energy levels and discovered AKT/FOXO regulated novel lipases that mobilize and integrate the use of triglycerides for energy consuming processes. Impairment of the function of these lipases leads to elevated triglycerides, increased sensitivity to starvation and cardiac dysfunction. Our data indicate the existence of a lipolytic pathway functioning across different organs that includes the two novel lipases and is active under both physiological and stress conditions. The goal of this proposal is to elucidate the mechanisitic details involved in the complex functioning of these lipases in physiological as well as pathological states that are associated with hypertriglyceridemia. The specific aims of this project are (1). Gain insight into the non-autonomous mode of action of CG8093 and CG6277 lipases (2). Identify components and pathways involved in the regulation of triglycerides by CG8093 and CG6277 through a genetic approach (3). Evaluate the role of CG8093 and G6277 lipases in hypertriglyceridemia associated with obesity and diabetes using Drosophila and mouse models. Upon completion of these aims, we hope to gain considerable insight into the mechanism of action of these lipases and their contribution to energy metabolism in physiological and stress conditions and identify components and pathways involved in the functioning of these lipases.

描述(申请人提供)：三酰甘油是脂肪酰辅酶A的来源，在生物体中作为能量储存。在压力和高能活动的条件下，它们被动员起来，以有效地产生能量。三酰甘油动员缺陷会导致几种人类疾病，如肥胖、代谢综合征，并是糖尿病和心血管疾病的并发症。鞘磷脂神经酰胺通过干扰线粒体功能影响细胞能量代谢。在一个积累神经酰胺的果蝇模型中，我们研究了它如何适应受损的能量水平，并发现AKT/FOXO调节的新型脂肪酶可以动员和整合甘油三酯的使用来消耗能量。这些脂肪酶的功能受损会导致甘油三酯升高，对饥饿和心脏功能障碍的敏感度增加。我们的数据表明，存在一个跨越不同器官的脂解途径，包括这两种新的脂肪酶，并且在生理和应激条件下都是活跃的。这项建议的目的是阐明这些脂肪酶在生理和病理状态下与高甘油三酯血症相关的复杂功能所涉及的机制细节。本项目的具体目标是(1)。深入了解CG8093和CG6277脂肪酶的非自主作用模式(2)。通过遗传方法确定CG8093和CG6277调节甘油三酯的成分和途径(3)。利用果蝇和小鼠模型评价CG8093和G6277脂肪酶在肥胖和糖尿病相关的高甘油三酯血症中的作用。随着这些目标的完成，我们希望深入了解这些脂肪酶的作用机制以及它们在生理和应激条件下对能量代谢的贡献，并确定参与这些脂肪酶功能的成分和途径。