Molecular mechanisms of intra- and inter-cellular fatty acid trafficking

细胞内和细胞间脂肪酸运输的分子机制

• 批准号: 10164808
• 负责人: Sarah Cohen
• 金额: $ 38.09万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164808
• 关键词: Address; Atherosclerosis; Biochemistry; Cachexia; Cells; Development; Disease; Environment; Essential Fatty Acids; Failure; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Goals; Image Analysis; Impairment; Lead; Lipids; Lipodystrophy; Lipoproteins; Liver diseases; Mediating; Membrane; Metabolic syndrome; Metabolism; Microscopy; Molecular; Molecular Biology; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Organelles; Proteins; Research; Resolution; Site; Techniques; Testing; Tissues; Triglycerides; Work; cell type; environmental change; exosome; fatty acid metabolism; human disease; nutrient deprivation; particle; response; trafficking; uptake

ABSTRACT Fatty acids are essential cellular lipids. They allow cells to store energy in a highly concentrated form and to build the membranes that separate cells from their environment. Both impaired and excess lipid storage can lead to human disease: failure to appropriately store fat leads to lipodystrophy and cachexia, while excess lipid storage is a hallmark of metabolic syndrome, type 2 diabetes, atherosclerosis, and fatty liver disease. The goal of our research is to address two fundamental questions about fatty acid trafficking. The first of these is: how do fatty acids traffic among organelles within a cell? Fatty acids are stored as triglycerides within organelles called lipid droplets. Emerging evidence indicates that fatty acids can transfer between lipid droplets and other organelles at sites of close apposition called membrane contact sites. However, the proteins that mediate lipid droplet-organelle contact sites are largely unknown. We will use candidate and unbiased approaches to identify proteins that mediate lipid droplet-organelle contact sites. We will then test the effect of modulating these proteins on fatty acid storage, trafficking, and metabolism. When organelle dynamics and fatty acid metabolism within a cell are impaired, cells may efflux excess fatty acids to their neighbors. Thus, the second question we will address is: how do fatty acids traffic between cells in a tissue? Several possible mechanisms exist, including direct transfer at cell-cell contacts; efflux of “free fatty acids” followed by uptake into a neighboring cell; and transfer of fatty acids via particles including lipoprotein particles and exosomes. We will investigate the mechanisms of intercellular fatty acid trafficking in response to nutrient deprivation and between different cell types. To address these questions, we will use a combination of techniques including molecular biology, biochemistry, cutting-edge multispectral and super resolution microscopy, and advanced image analysis approaches. Together, these studies will elucidate molecular mechanisms of fatty acid trafficking within and between cells, in response to changing environmental and developmental conditions. A better understanding of these mechanisms will have implications for both diseases of impaired and excess lipid storage.

抽象的 脂肪酸是必需的细胞脂质。它们允许细胞以高度浓缩的形式存储能量，并 建立将细胞与环境分开的机制。受损和超过脂质存储都可以 导致人类疾病：无法适当储存脂肪会导致脂肪营养不良和恶病质，而超过 脂质储存是代谢综合征，2型糖尿病，动脉粥样硬化和脂肪肝病的标志。 我们研究的目的是解决有关脂肪酸贩运的两个基本问题。第一个 这些是：细胞内细胞器之间的脂肪酸如何流动？脂肪酸被储存为甘油三酸酯 在称为脂质液滴的细胞器中。新兴的证据表明脂肪酸可以在 在密切占用位置的脂质液滴和其他细胞器称为膜接触部位。但是， 介导脂质液滴 - 轨道接触位点的蛋白质在很大程度上未知。我们将使用候选人， 无偏的方法鉴定介导脂质液滴 - 轨道接触位点的蛋白质。然后我们将测试 调节这些蛋白质对脂肪酸储存，运输和代谢的影响。当细胞器时 细胞内的动力学和脂肪酸代谢受损，细胞可能会出现超过脂肪酸。 邻居。我们将要解决的第二个问题是：脂肪酸如何在组织中的细胞之间流动？ 存在几种可能的机制，包括在细胞细胞接触处的直接转移； “游离脂肪酸”的外排 然后摄取进入相邻的细胞；并通过包括脂蛋白在内的颗粒转移脂肪酸 颗粒和外泌体。我们将研究响应细胞间脂肪酸运输的机制 营养剥夺和不同细胞类型之间。为了解决这些问题，我们将使用 包括分子生物学，生物化学，尖端多光谱和超级技术在内的技术组合 分辨率显微镜和高级图像分析方法。这些研究将共同​​阐明 脂肪酸在细胞内部和细胞之间运输的分子机制，以响应变化 环境和发展条件。更好地了解这些机制 对受损和超过脂质储存的两种疾病的影响。