Regulation and consequences of hepatic lipid droplet catabolism

肝脏脂滴分解代谢的调节和后果

• 批准号: 9926393
• 负责人: Douglas G Mashek
• 金额: $ 6.23万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926393
• 关键词: Ablation; Address; Adipose tissue; Affect; American; Autophagocytosis; Autophagosome; Binding; Cardiovascular Diseases; Catabolism; Cell Nucleus; Cell membrane; Cell model; Cell physiology; Cells; Characteristics; Chemicals; Circadian Rhythms; Comorbidity; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Deacetylase; Development; Diet; Disease; Energy Metabolism; Etiology; FOXO1A gene; Fatty Acids; Fatty acid glycerol esters; Genetic Transcription; Glean; Glucagon; Goals; Health; Hepatic; Hormones; Human; In Situ; Insulin; Laboratories; Life Style; Link; Lipase; Lipids; Lipolysis; Liver; Liver diseases; Lysosomes; Mediating; Metabolic Diseases; Metabolism; Modeling; Non-Insulin-Dependent Diabetes Mellitus; Oleates; Organelles; PPAR alpha; Pathway interactions; Pharmacologic Substance; Physiological; Prevalence; Primary carcinoma of the liver cells; Process; Property; Proteins; Publishing; Regulation; Risk; Role; SIRT1 gene; Signal Transduction; Steatohepatitis; TRP channel; Testing; Therapeutic; Triglycerides; Work; arm; base; hepatic lipase; in vitro Model; in vivo; innovation; lipid metabolism; mouse model; non-alcoholic fatty liver disease; novel; overexpression; oxidation; perilipin; prevent; response; small molecule; targeted treatment; therapeutic target; trafficking

PROJECT SUMMARY Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and is tightly linked to numerous metabolic diseases. Lipid droplet (LDs) are the major storage organelles of intracellular triacylglycerol (TAG) and, therefore, are the defining characteristic of NAFLD. In contrast to historical views of LDs as simply inert forms of energy storage, recent studies have identified LDs as important organelles that influences cellular function and signaling in addition to the regulation of TAG content and turnover. Given the prevalence of NAFLD and its massive burden worldwide, understanding the mechanisms governing LD metabolism is paramount if we aim to progress to effective dietary, lifestyle or pharmaceutical therapies targeting NAFLD and its comorbidities. This application will build upon recent findings from our laboratory regarding the role of adipose triglyceride lipase (ATGL) in liver energy metabolism. Our published and preliminary data show that ATGL is a major hepatic lipase that promotes oxidation of hydrolyzed fatty acids (FAs) and links cAMP/PKA signaling to sirtuin 1 (SIRT1)-mediated induction of PGC-1a and its transcriptional binding partners (e.g. PPAR-a and FoxO1). Once activated in response to ATGL, SIRT1 promotes autophagy/lipophagy, which in turn is responsible for bulk degradation of hepatic LDs and the subsequent efflux of FAs. Based on this data, the objective of this proposal is to elucidate the physiological and mechanistic regulation of lipophagy and trafficking of lysosome-derived FAs. We hypothesize that ATGL, via intracellular trafficking of oleate, activates SIRT1 to control specific arms of lipophagy leading to LD catabolism and lysosomal-mediated FA efflux. To test our hypothesis, we will conduct the following specific aims: 1) to characterize the physiological regulation of and interplay between ATGL and lipophagy/FA efflux; 2) to define the mechanism linking ATGL to SIRT1 signaling and lipophagy induction; and 3) to elucidate the regulation and consequences of lysosomal-mediated FA efflux on hepatic energy metabolism. Aim 1 will employ cell, perfused liver and mouse models to characterize how physiological factors regulate lipophagy. Aim 2 will use both cell and mouse models to dissect out the signaling network linking ATGL to the regulation of autophagy/lipophagy and FA efflux. Aim 3 will focus on lysosome fusion to the plasma membrane as a therapeutic target to increase lipophagy. These studies are innovative in that they will answer novel questions about the regulation of LD catabolism and signaling. This work is significant because it advances our understanding of the defining characteristic of NAFLD (i.e. LDs), which will have a positive and sustained impact towards the goal of preventing or treating NAFLD and related comorbidities.

项目摘要 非酒精性脂肪肝病（NAFLD）是全球最常见的肝病，与 许多代谢疾病。脂质液滴（LDS）是细胞内的主要存储细胞器 三酰基甘油（TAG），因此是NAFLD的定义特征。与历史观点相反 LDS简称为惰性储能的形式，最近的研究确定LDS是重要的细胞器 除了调节标签含量和周转外，还影响细胞功能和信号传导。鉴于 NAFLD及其在全球范围内的巨大负担的盛行，了解ld的机制 如果我们旨在发展有效的饮食，生活方式或药物疗法，代谢至关重要 针对NAFLD及其合并症。该申请将基于我们实验室的最新发现 关于脂肪甘油三酸酯脂肪酶（ATGL）在肝能量代谢中的作用。我们出版的 初步数据表明，ATGL是促进水解脂肪酸氧化的主要肝脂肪酶 （FAS）并将CAMP/PKA信号链接到SIRTUIN 1（SIRT1）介导的PGC-1A及其转录 绑定伙伴（例如PPAR-A和FOXO1）。一旦响应ATGL激活，SIRT1就会促进 自噬/脂肪噬菌，这反过 Fas的外排。基于此数据，该提案的目的是阐明生理和 脂肪体的机械调节和溶酶体衍生的FA的运输。我们假设ATGL通过 Oleate的细胞内贩运，激活SIRT1以控制脂肪的特定臂，导致LD分解代谢 和溶酶体介导的FA外排。为了检验我们的假设，我们将执行以下特定目的：1） 表征ATGL和脂肪/FA外排之间的生理调节和相互作用； 2）定义 将ATGL连接到SIRT1信号传导和寄生诱导的机制； 3）阐明法规和 溶酶体介导的FA外排对肝能量代谢的后果。 AIM 1将使用细胞，灌注 肝脏和小鼠模型以表征生理因素如何调节寄生虫。 AIM 2将使用两个单元格 和鼠标模型，以剖析将ATGL连接到自噬/亲脂的信号网络 和FA外排。 AIM 3将重点介绍溶酶体融合到质膜，作为增加的靶标 脂肪。这些研究具有创新性，因为它们将回答有关LD调节的新颖问题 分解代谢和信号传导。这项工作很重要，因为它可以提高我们对定义的理解 NAFLD的特征（即LDS），这将对目标产生积极和持续的影响 防止或治疗NAFLD及其相关合并症。