Lysosome‐Lipid Droplet Interactions in Fatty Acid Metabolism

脂肪酸代谢中的溶酶体与脂滴相互作用

• 批准号: 10501725
• 负责人: Jing Pu
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10501725
• 关键词: Cell physiology; Cells; Cellular Metabolic Process; Digestion; Disease Progression; Genetic Screening; Hepatocyte; High Prevalence; Homeostasis; Human; Intervention; Intracellular Membranes; Knowledge; Lipid Mobilization; Lipids; Liver; Lysosomes; Mediating; Membrane; Membrane Lipids; Metabolic Diseases; Molecular; Names; Nonesterified Fatty Acids; Normal Cell; Organelles; Pathology; Physiological; Play; Prevention; Process; Proteins; Regulation; Role; Site; Source; Testing; Tissues; Toxic effect; Work; Yeasts; design; extracellular; fatty acid metabolism; fatty acid transport; lipid transport; mouse model; non-alcoholic fatty liver disease; novel; prevent; protein protein interaction; vector

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.

溶酶体和脂质液滴之间的相互作用代表脂质动员的过程 和细胞代谢和脂质稳态所需的能量。用于脂质降解的脂肪噬菌是一个 已知类型的溶酶体 - 脂质液滴相互作用。我们的初步研究和其他结果表明 有第二种类型的溶酶体脂质液滴相互作用，它介导了从 溶酶体与脂质液滴进行脂质合成和储存。这个过程可能是由 有组织的细胞器膜接触位点（MCS）有组织的细胞器 通过蛋白质 - 蛋白质和蛋白质脂质相互作用。 MC提供脂质的矢量运输 异源细胞器，并因其在脂质稳态中的作用而受到赞赏。我们的小组 将研究溶酶体 - 脂质液滴相互作用，并在溶酶体 - 脂质液滴MC的焦点 脂肪酸代谢。细胞内游离脂肪酸的调节对于正常细胞功能至关重要，因为 过量的胞质游离脂肪酸会对细胞和组织（命名为脂肪毒性）产生毒性作用，从而导致 在许多代谢性疾病中被认为是病因因素，包括非酒精脂肪 肝病（NAFLD）。溶酶体是胞质游离脂肪酸的一种来源，它释放自由脂肪 消化内吞细胞外脂质以及自噬内膜和脂质后的酸。 将游离脂肪酸的传输和存储增加到脂质液滴中可以保护细胞，包括肝脏 细胞，来自脂肪毒性。因此，溶酶体 - 液滴液滴MC可能在预防中起重要作用 溶酶体游离脂肪酸诱导的脂肪毒性。但是，尚不清楚MC是否存在 溶酶体和脂质液滴以及溶酶体 - 脂肪液滴MC是否具有游离脂肪酸。 此外，尚不清楚溶酶体脂质液滴MC是否在防止溶酶体 - 触发脂肪毒性并调节脂肪酸代谢。我们最近的研究支持存在 人肝细胞中的溶酶体脂质液滴MC，我们确定了蛋白质 - 蛋白质相互作用 通过酵母中的遗传筛选，溶酶体脂质液滴MC。在接下来的五年中，我们将定义 主要成分和溶酶体 - 脂质液滴MC的功能，并测试是否促进MCS形成 将预防或降低小鼠模型中的脂肪毒性，从而预防NAFLD进展。通过调查 溶酶体 - 脂质液滴MC的功能，机制和生理功能，我们的工作将揭示 以前溶酶体与脂质液滴之间的不确定的相互作用并发现了一种新型机制 游离脂肪酸的转运。这种机制将加深对脂肪酸代谢的理解， 脂肪毒性和NAFLD的病理。