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

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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.