Lysosome‐Lipid Droplet Interactions in Fatty Acid Metabolism

溶酶体和脂滴之间的相互作用代表了脂类的动员过程。 以及细胞新陈代谢和脂类平衡所需的能量。吞脂术是一种降解脂肪的方法。 已知类型的溶酶体-脂滴相互作用。我们的初步研究和其他人的结果表明 还有第二种类型的溶酶体-脂滴相互作用，它介导脂类从 溶酶体到脂滴，用于脂类的合成和储存。这一过程可能是由 细胞器膜接触部位(MCS)，最近被定义为系系细胞器，有组织 通过蛋白质-蛋白质和蛋白质-脂质相互作用。MCS提供脂类在 异源细胞器，并因其在脂质稳态中的作用而日益受到重视。我们的团队 将在以下背景下研究溶酶体-脂滴与溶酶体-脂滴MCS的相互作用 脂肪酸代谢。细胞内游离脂肪酸的调节对细胞的正常功能至关重要，因为 过量的胞内游离脂肪酸会对细胞和组织产生毒性效应(称为脂毒性)，因此 已被认为是许多代谢紊乱的致病因素，包括非酒精性脂肪 肝病(NAFLD)。胞质游离脂肪酸的一个来源是溶酶体，它释放游离脂肪 消化内吞的胞外脂和自噬的胞内膜和脂类后的酸性物质。 增加游离脂肪酸到脂滴中的运输和储存可以保护细胞，包括肝脏 细胞，来自脂肪毒性。因此，溶酶体-脂滴MCS可能在预防高血压病中发挥重要作用。 溶酶体游离脂肪酸引起的脂毒性。然而，尚不清楚MCS是否存在于 溶酶体和脂滴以及溶酶体-脂滴MCS是否运输游离脂肪酸。 此外，目前尚不清楚溶酶体-脂滴MCS是否在预防溶酶体-脂滴中发挥作用。 触发脂肪毒性，调节脂肪酸代谢。我们最近的研究支持了 人肝细胞中的溶酶体-脂滴MCS，我们在 酵母菌中通过遗传筛选的溶酶体-脂滴MCS。在未来五年，我们将定义 溶酶体-脂滴MCS的主要成分和功能，以及是否促进MCS的形成 将防止或减少脂肪毒性，从而在小鼠模型中NAFLD的进展。通过调查 溶酶体-脂滴MCS的特征、机制和生理功能，我们的工作将揭示 溶酶体和脂滴之间以前未知的相互作用并揭示了一种新的机制 自由脂肪酸的运输。这一机制将加深对脂肪酸代谢的认识， 脂肪毒性，以及NAFLD的病理。

The interactions between lysosomes and lipid droplets represent the processes of mobilization of lipids and energy required for cell metabolism and lipid homeostasis. Lipophagy, for lipid degradation, is a known type of lysosome-lipid droplet interaction. Our preliminary studies and results from others suggest there is a second type of lysosome-lipid droplet interaction, which mediates lipid transport from lysosomes to lipid droplets for lipid synthesis and storage. This process is probably mediated by the organelle membrane contact sites (MCS), which are recently defined as tethered organelles, organized by protein-protein and protein-lipid interactions. MCS provide vectorial transport of lipids between heterologous organelles and are increasingly appreciated for their role in lipid homeostasis. Our group will study lysosome-lipid droplet interactions with a focus of lysosome-lipid droplet MCS in the context of fatty acid metabolism. Regulation of free fatty acids within the cell is critical for normal cell functions, as excess cytosolic free fatty acids cause toxic effects to cells and tissues (named lipotoxicity) and thus have been recognized as a causative factor in many metabolic disorders, including non-alcoholic fatty liver disease (NAFLD). One source of cytosolic free fatty acids is the lysosome, which releases free fatty acids after digesting endocytosed extracellular lipids and autophagic intracellular membranes and lipids. Increasing the transport and storage of free fatty acids into lipid droplets protects cells, including liver cells, from lipotoxicity. Therefore, lysosome-lipid droplet MCS may play an important role in prevention of lysosomal free fatty acid-induced lipotoxicity. However, it is not clear whether MCS exist between lysosomes and lipid droplets and whether lysosome-lipid droplet MCS transport free fatty acids. Moreover, it is not known whether lysosome-lipid droplet MCS play a role in preventing lysosome- triggered lipotoxicity and regulating fatty acid metabolism. Our recent studies support the existence of lysosome-lipid droplet MCS in human liver cells, and we identified the protein-protein interactions at lysosome-lipid droplet MCS through a genetic screening in yeast. In the next five years, we will define the principal components and function of lysosome-lipid droplet MCS, and test if promoting MCS formation will prevent or reduce lipotoxicity and thus NAFLD progression in a mouse model. By investigating the features, mechanisms, and physiological functions of lysosome-lipid droplet MCS, our work will reveal a previously undefined interaction between lysosomes and lipid droplets and uncover a novel mechanism of free fatty acid transport. This mechanism will deepen the understandings to fatty acid metabolism, lipotoxicity, and the pathology of NAFLD.