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: 9980935
• 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/9980935
• 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.

摘要 脂肪酸是必需的细胞脂类。它们允许细胞以高度集中的形式储存能量，并 构建将细胞与其环境分开的膜。脂肪储存受损或过多都会 导致人类疾病：未能适当储存脂肪会导致脂肪营养不良和恶病质，而脂肪过量 脂肪储存是代谢综合征、2型糖尿病、动脉粥样硬化和脂肪肝的标志。 我们研究的目标是解决有关脂肪酸贩运的两个基本问题。第一个 这些是：脂肪酸是如何在细胞内细胞器之间进行运输的？脂肪酸以甘油三酯的形式储存。 在细胞器中称为脂滴。新的证据表明，脂肪酸可以在 脂滴和其他细胞器在紧密结合的部位称为膜接触部位。然而， 调节脂滴-细胞器接触部位的蛋白质在很大程度上是未知的。我们将使用Candiate和 无偏见的方法，以确定调节脂滴-细胞器接触部位的蛋白质。然后我们将测试 调节这些蛋白质对脂肪酸储存、运输和新陈代谢的影响。当细胞器 细胞内的动力学和脂肪酸代谢受到损害，细胞可能会将多余的脂肪酸排出到细胞内 邻里。因此，我们将解决的第二个问题是：脂肪酸是如何在组织中的细胞之间进行运输的？ 存在几种可能的机制，包括细胞-细胞接触的直接转移；“游离脂肪酸”的外流。 然后被邻近的细胞摄取；以及通过包括脂蛋白在内的颗粒转移脂肪酸 颗粒和外周小体。我们将研究细胞间脂肪酸运输的机制作为回应 营养缺乏和不同细胞类型之间的关系。为了解决这些问题，我们将使用 结合了分子生物学、生物化学、尖端多光谱和超 分辨率显微镜和先进的图像分析方法。总之，这些研究将阐明 脂肪酸在细胞内和细胞间运输的分子机制 环境和发展条件。对这些机制的更好理解将会有 对脂肪储存受损和过度储存的疾病都有影响。