Adaptation to ceramide involves AKT/FOXO regulated novel triglyceride lipases

 性状（由申请人提供）：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。它们在压力和高能量活动的条件下被调动起来，以有效地生产能量。动员三酰甘油的缺陷导致几种人类疾病，如肥胖症、代谢综合征，并且是糖尿病和心血管疾病的并发症。鞘脂神经酰胺通过干扰线粒体功能影响细胞能量代谢。在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，并发现了AKT/FOXO调节的新型脂肪酶，这些脂肪酶可动员和整合甘油三酯用于能量消耗过程。这些脂肪酶的功能受损导致甘油三酯升高，对饥饿和心脏功能障碍的敏感性增加。我们的数据表明，存在一个脂肪分解途径，在不同的器官，其中包括两个新的脂肪酶，是积极的生理和压力条件下。该建议的目的是阐明这些脂肪酶在与高胆固醇血症相关的生理和病理状态中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CG 8093和CG 6277脂肪酶的非自主作用模式（2）。通过遗传方法确定CG 8093和CG 6277调节甘油三酯的组分和途径（3）。使用果蝇和小鼠模型评价CG 8093和G6277脂肪酶在与肥胖和糖尿病相关的高脂血症中的作用。在完成这些目标后，我们希望能够深入了解这些脂肪酶的作用机制及其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组分和途径。

 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.