Mechanisms of lipophagy, the selective autophagy of lipid droplets

脂肪自噬机制，脂滴的选择性自噬

• 批准号: 9141938
• 负责人: Taras Y. Nazarko
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-04 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9141938
• 关键词: Address; Aging; Area; Atherosclerosis; Autophagocytosis; Cytosol; Data; Disease; Eukaryotic Cell; Fatty Liver; Fatty acid glycerol esters; Human; Lipids; Lysosomes; Lytic; Mammalian Cell; Mammals; Membrane; Metabolic syndrome; Modeling; Molecular; Mus; Obesity; Pathway interactions; Prevention; Proteins; Proteome; Recycling; Regulation; Repression; Research; Rest; Role; Time; Up-Regulation; Vacuole; Yeasts; Zebrafish; abstracting; lipid metabolism; macrophage; novel; programs; therapeutic target; tool

Project Summary/Abstract Lipophagy, the selective autophagy of lipid droplets (LDs), is an essential mechanism that regulates the intracellular lipid metabolism in most eukaryotic cells. Lipophagy is accomplished by the delivery of LDs from the cytosol to the lytic compartment (lysosome in mammals or vacuole in yeast). As in other autophagic pathways, the core autophagic machinery forms the autophagic isolation membrane that sequesters the LD from the cytosol. However, how this autophagic membrane recognizes the LD when lipophagy is induced is unknown. Also, it is not clear how lipophagy is kept in check the rest of the time. Therefore, lipophagy selectivity and regulation are the key gaps in our understanding of this autophagic pathway. The mechanistic understanding in these areas is critical for the precise control of lipophagy in humans for the prevention and treatment of a whole plethora of lipid accumulation diseases, including fatty liver, metabolic syndrome of aging, obesity and atherosclerosis. Recently, we discovered a novel negative regulator of lipophagy 1 (Nrl1) that specifically represses lipophagy but not non-selective autophagy in yeast. Our preliminary data suggest that the function of Nrl1 is conserved from yeast to mammalian cells and that it promotes the accumulation of LDs in murine macrophages. Since a specific suppressor of lipophagy would be such a good therapeutic target for upregulation of the pathway in so many disease states, the first project of our research program will be dedicated to the regulation of lipophagy by Nrl1. We will study the molecular mechanism of lipophagy repression by Nrl1, how specific it is for the lipophagy pathway and the impact of Nrl1 on lipid metabolism at both the cellular (yeast and macrophages) and organismal (zebrafish) levels. The second project of our research program will be focused on the selectivity mechanisms of lipophagy. By tracking down the regulatory effects of Nrl1, we will identify its effectors, the lipophagy-specific selectivity factors. We will also extend the selectivity studies to the LD proteome and identify the selectivity factors that might be regulated in an Nrl1- independent fashion. Comprehensive analyses of the lipophagy-specific factors is an important challenge to be addressed, since such factors define the lipophagy pathway, can be used to control it and are expected to be the new autophagic proteins. The evolutionary conserved lipophagy factors will be studied further at both the cellular (yeast and macrophages) and organismal (zebrafish) levels. We will generate lipophagy-deficient zebrafish models that together with the nrl1 model of constitutive lipophagy will constitute new valuable tools to address the specific contribution of lipophagy to various lipid accumulation diseases.

项目总结/摘要 脂质吞噬，即脂滴（LDs）的选择性自噬，是调节细胞增殖的重要机制。 大多数真核细胞的细胞内脂质代谢。脂肪吞噬是通过递送LD完成的， 胞质液进入裂解区（哺乳动物中的溶酶体或酵母中的液泡）。就像其他自噬动物一样 在自噬通路中，核心自噬机制形成了隔离LD的自噬隔离膜 从细胞质中分离出来然而，当脂肪吞噬被诱导时，这种自噬膜如何识别LD， 未知此外，尚不清楚如何在其余时间内控制脂肪吞噬。因此， 选择性和调节是我们理解这种自噬途径的关键差距。机械论 了解这些领域对于精确控制人类的脂肪吞噬以预防和 治疗多种脂质积聚疾病，包括脂肪肝，衰老代谢综合征， 肥胖和动脉粥样硬化。最近，我们发现了一种新的脂肪吞噬负调节因子1（Nrl 1）， 特异性抑制酵母中的脂肪吞噬，但不抑制非选择性自噬。我们的初步数据显示， 从酵母到哺乳动物细胞，Nrl 1的功能是保守的，它促进LD的积累 在小鼠巨噬细胞中。由于脂肪吞噬的特异性抑制剂将是一个很好的治疗靶点， 在许多疾病状态下上调通路，我们研究计划的第一个项目将是 致力于通过Nrl 1调节脂肪吞噬。我们将研究噬脂作用的分子机制 Nrl 1的抑制，它对脂肪吞噬途径的特异性以及Nrl 1对脂质代谢的影响， 细胞（酵母和巨噬细胞）和生物体（斑马鱼）水平。我们的第二个项目 研究计划将集中在脂肪吞噬的选择性机制。通过追踪监管机构 Nrl 1的影响，我们将确定其效应，脂肪吞噬特异性选择性因子。我们亦会延长 LD蛋白质组的选择性研究，并确定可能在Nrl 1- 独立时尚对噬脂细胞特异性因子的综合分析是一个重要的挑战， 由于这些因子定义了脂肪吞噬途径，因此可以用于控制它，并且预计将 新的自噬蛋白进化上保守的噬脂因子将在两个方面进一步研究。 细胞（酵母和巨噬细胞）和生物体（斑马鱼）水平。我们会产生缺乏脂肪吞噬的 斑马鱼模型与nrl 1组成性脂肪吞噬模型一起将构成新的有价值的工具， 解决了脂肪吞噬对各种脂质积累疾病的具体贡献。