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.

溶酶体和脂滴之间的相互作用代表了脂质动员的过程 以及细胞代谢和脂质稳态所需的能量。脂肪自噬，用于脂质降解，是一种 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，它介导脂质从 溶酶体形成脂滴，用于脂质合成和储存。这个过程可能是由 细胞器膜接触位点（MCS），最近被定义为系留细胞器，组织 通过蛋白质-蛋白质和蛋白质-脂质相互作用。 MCS 提供脂质之间的矢量运输 异源细胞器，并因其在脂质稳态中的作用而日益受到重视。我们组 将在以下背景下以溶酶体-脂滴 MCS 为重点研究溶酶体-脂滴相互作用 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产生毒性作用（称为脂毒性），从而 已被认为是许多代谢紊乱的致病因素，包括非酒精性脂肪 肝脏疾病（NAFLD）。胞质游离脂肪酸的来源之一是溶酶体，它释放游离脂肪 消化内吞的细胞外脂质和自噬细胞内膜和脂质后产生的酸。 增加游离脂肪酸在脂滴中的运输和储存，保护细胞，包括肝脏 细胞，免受脂毒性。因此，溶酶体-脂滴MCS可能在预防 溶酶体游离脂肪酸诱导的脂毒性。然而，尚不清楚之间是否存在MCS 溶酶体和脂滴以及溶酶体-脂滴 MCS 是否转运游离脂肪酸。 此外，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。 引发脂毒性并调节脂肪酸代谢。我们最近的研究支持存在 人类肝细胞中的溶酶体-脂滴MCS，我们鉴定了蛋白质-蛋白质相互作用 通过酵母基因筛选获得溶酶体脂质滴 MCS。未来五年，我们将定义 溶酶体脂滴MCS的主要成分和功能，并测试是否促进MCS形成 将预防或减少小鼠模型中的脂毒性，从而预防 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 先前未定义的溶酶体和脂滴之间的相互作用并揭示了一种新的机制 游离脂肪酸运输。这一机制将加深对脂肪酸代谢的理解， 脂毒性和 NAFLD 的病理学。