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.

摘要 脂肪酸是细胞必需的脂类。它们允许细胞以高度集中的形式储存能量， 构建将细胞与环境分离的膜。脂质储存受损和过量都可能 导致人类疾病：未能适当储存脂肪会导致脂肪代谢障碍和恶病质，而过量储存脂肪则会导致脂肪代谢障碍和恶病质 脂质蓄积是代谢综合征、2型糖尿病、动脉粥样硬化和脂肪肝疾病的标志。 我们研究的目标是解决关于脂肪酸运输的两个基本问题。中的第一 这些问题是：脂肪酸如何在细胞内的细胞器之间运输？脂肪酸以甘油三酯的形式储存 在叫做脂滴的细胞器中。新出现的证据表明，脂肪酸可以在 脂滴和其他细胞器在被称为膜接触位点的紧密并置位点。但 介导脂滴-细胞器接触位点的蛋白质在很大程度上是未知的。我们将使用候选人和 无偏的方法来鉴定介导脂滴-细胞器接触位点的蛋白质。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 当细胞内的动力学和脂肪酸代谢受损时，细胞可以将过量的脂肪酸流出到它们的细胞中。 邻居因此，我们要解决的第二个问题是：脂肪酸如何在组织中的细胞之间运输？ 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”的流出 随后被摄取到邻近细胞中;以及通过包括脂蛋白的颗粒转移脂肪酸 粒子和外来体。我们将研究细胞间脂肪酸运输的机制， 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、尖端多光谱和超光谱等技术， 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 细胞内和细胞间脂肪酸运输的分子机制， 环境和发展条件。更好地理解这些机制将有助于 这两种疾病的损害和过量的脂质储存的影响。