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中文摘要
翻译
溶酶体和脂滴之间的相互作用代表了脂质的动员过程 以及细胞代谢和脂质体内平衡所需的能量。对于脂质降解, 已知类型溶酶体-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,其介导脂质从 溶酶体到脂滴用于脂质合成和储存。这一过程可能是由 细胞器膜接触位点(MCS),最近被定义为系留细胞器, 通过蛋白质-蛋白质和蛋白质-脂质相互作用。MCS提供了脂质在 异源细胞器,并越来越多地认识到其在脂质体内平衡中的作用。我们集团 将研究溶酶体-脂滴相互作用,重点是溶酶体-脂滴MCS, 脂肪酸代谢细胞内游离脂肪酸的调节对正常细胞功能至关重要, 过量的胞质游离脂肪酸引起对细胞和组织的毒性作用(称为脂毒性 已经被认为是许多代谢紊乱的致病因素,包括非酒精性脂肪性疾病, 肝病(NAFLD)。胞质游离脂肪酸的一个来源是溶酶体,其释放游离脂肪酸, 消化内吞的细胞外脂质和自噬细胞内膜和脂质后的酸。 增加游离脂肪酸进入脂滴的运输和储存保护细胞,包括肝脏 细胞,从脂毒性。因此,溶酶体-脂滴MCS可能在预防肝硬化中起重要作用。 溶酶体游离脂肪酸诱导的脂毒性。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是否转运游离脂肪酸。 此外,尚不清楚溶酶体-脂滴MCS是否在阻止溶酶体-脂滴MCS中起作用。 引发脂毒性和调节脂肪酸代谢。我们最近的研究支持了 溶酶体-脂滴MCS在人类肝细胞中,我们确定了蛋白质-蛋白质相互作用, 溶酶体-脂滴MCS通过酵母中的遗传筛选。在未来五年,我们将确定 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并因此预防或减少NAFLD进展。通过调查 溶酶体-脂滴MCS的特点、机制和生理功能,我们的工作将揭示一个 以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, 自由脂肪酸运输的。这一机制将加深对脂肪酸代谢的认识, 脂毒性和NAFLD的病理学。
英文摘要
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.
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会议论文
Lysosome‐Lipid Droplet Interactions in Fatty Acid Metabolism
Lysosome Dynamics-Regulated Lipid Metabolism in Pancreatic Cancer
Lysosome Dynamics-Regulated Lipid Metabolism in Pancreatic Cancer
Lysosome Dynamics-Regulated Lipid Metabolism in Pancreatic Cancer
国内基金
海外基金
分化肌细胞脱细胞ECM-cells sheet 3D 支架构建及其促进容积性肌组织缺损再 生修复应用及机制研究
CAFs-TAMs-tumor cells调控在HRHPV感染致癌中的作用机制研究及AI可追溯预测模型建立
  • 批准号:
    82072862
  • 项目类别:
    面上项目
  • 资助金额:
    56.0万元
  • 批准年份:
    2020
  • 负责人:
    徐云升
  • 依托单位:
S100A8/A9--Myeloid cells特异性可溶性表氧化物水解酶(sEH)基因敲除改善胰岛素抵抗的新靶点
  • 批准号:
    82070825
  • 项目类别:
    面上项目
  • 资助金额:
    53.0万元
  • 批准年份:
    2020
  • 负责人:
    徐西振
  • 依托单位:
Leader cells通过CCL5调控糖酵解及基质硬度促进结直肠癌集体侵袭的 作用机制
  • 批准号:
    81903002
  • 项目类别:
    青年科学基金项目
  • 资助金额:
    20.5万元
  • 批准年份:
    2019
  • 负责人:
    王斐斐
  • 依托单位: