Mechanisms of Lipid Heterogeneity in Lipid Droplet Catabolism

项目总结：“脂滴分解代谢中的脂类异质性机制” 脂滴(LD)分解代谢是推动迁移等能量密集型细胞任务的基本过程， 分化，以及通过低养分可获得性时期的生存。异常的LD分解代谢在 几种疾病的病理，包括脂肪肝、肥胖症、糖尿病、肾病和癌症。因为LD 分解代谢在细胞行为中起着基础性的作用，对这一过程的详细机制知识 有可能揭示潜在治疗的新靶点。该项目将确定细胞通过哪些机制 访问存储的LD燃料。低密度脂蛋白通过在几乎每个细胞中储存细胞内脂肪，在细胞新陈代谢中发挥关键作用 跨多个物种进行输入。在独特的磷脂单分子层的包围下，LDS含有丰富的中性 三酰甘油(TAG)和胆固醇酯(CE)形式的脂类，可通过 线粒体β氧化。这些储存的脂质的释放需要两个分解代谢过程之间的协同作用：1) 脂肪分解，其中β-肾上腺素能/cAMP刺激招募细胞质脂肪酶脂肪甘油三酯脂肪酶 (ATGL)到LD表面，以及2)脂噬，这是分解代谢的终末阶段，LD被贩卖用于 溶酶体通过自噬和/或内吞体小泡降解。我们实验室的初步数据支持 我们的中心假设是，LD单层内的脂质物种受到脂解和脂噬作用的调节 LD分解代谢过程中的酶。在目标1中，我们将确定脂解酶ATGL在生产 在目标2中，我们将确定 LD转运至溶酶体过程中磷脂酰肌醇磷酸化的调节。从以下方面获得的结果： 拟议的研究将提供对脂滴运输和分解代谢作为一种 激光二极管单层调制的结果。此外，这项研究将有助于未来更大规模的发展 研究项目资助申请。

Project Summary: "Mechanisms of Lipid Heterogeneity in Lipid Droplet Catabolism" Lipid droplet (LD) catabolism is a fundamental process that fuels energy-intensive cellular tasks like migration, differentiation, and survival through periods of low nutrient availability. Aberrant LD catabolism is recognized in several disease pathologies including fatty liver, obesity, diabetes, kidney disease and cancer. Because LD catabolism plays a foundational role in cell behavior, detailed mechanistic knowledge of this process has the potential to reveal novel targets for potential therapy. This project will determine mechanisms by which cells access the stored LD fuel. LDs play critical roles in cell metabolism by storing intracellular fat in nearly every cell type across multiple species. Surrounded by a unique phospholipid monolayer, LDs contain abundant neutral lipids in the form of triacylglycerol (TAG) and cholesterol ester (CE) that can be utilized for energy production via mitochondrial β-oxidation. Release of these stored lipids requires synergy between two catabolic processes: 1) lipolysis, in which β-adrenergic/cAMP stimulation recruits the cytoplasmic lipase adipose triglyceride lipase (ATGL) to the LD surface, and 2) lipophagy, a terminal stage of catabolism in which LDs are trafficked for lysosomal degradation via autophagic and/or endosomal vesicles. Preliminary data from our laboratory supports our central hypothesis that lipid species within the LD monolayer are modulated by lipolysis and lipophagy enzymes during LD catabolism. In Aim 1, we will determine the role of the lipolysis enzyme ATGL in producing DAG on the LD surface to recruit DAG effectors such as protein kinase C. In Aim 2, we will determine the regulation of phosphatidylinositol phosphorylation during LD trafficking to lysosomes. The results gained from the proposed research will provide a mechanistic understanding of lipid droplet trafficking and catabolism as a result of modulation of the LD monolayer. Moreover, this research will aid in future development of larger research project grant applications.