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: 9366252
• 负责人: Douglas G Mashek
• 金额: $ 37.68万
• 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/9366252
• 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; 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 非酒精性脂肪性肝病（NAFLD）是全球最常见的肝病，与以下疾病密切相关： 多种代谢性疾病。脂滴（Lipid droplet，LD）是细胞内重要的储存细胞器 三酰甘油（TAG），因此是NAFLD的定义特征。与历史观点相反， LD只是能量储存的惰性形式，最近的研究已经确定LD是重要的细胞器， 除了调节TAG含量和周转之外，还影响细胞功能和信号传导。鉴于 NAFLD的患病率及其在全球范围内的巨大负担，了解LD的控制机制 如果我们的目标是发展到有效的饮食，生活方式或药物治疗，新陈代谢是至关重要的 针对NAFLD及其合并症。这项应用将建立在我们实验室最近的发现之上 关于脂肪甘油三酯脂肪酶（ATGL）在肝脏能量代谢中的作用。我们的出版和 初步数据表明，ATGL是一种主要的肝脂肪酶，可促进水解脂肪酸的氧化 (FAs)并将cAMP/PKA信号传导与sirtuin 1（SIRT 1）介导的PGC-1a诱导及其转录调控联系起来。 结合配偶体（例如PPAR-a和FoxO 1）。一旦响应ATGL被激活，SIRT 1促进 自噬/脂肪吞噬，这反过来又负责肝脏LD的大量降解和随后的降解。 FAs的外排。基于这些数据，本提案的目的是阐明生理和 溶酶体衍生的FA的脂肪吞噬和运输的机械调节。我们假设ATGL，通过 油酸盐的细胞内运输，激活SIRT 1以控制导致LD催化剂的脂肪吞噬的特定臂 和溶酶体介导的FA流出。为了验证我们的假设，我们将进行以下具体目标：1） 表征ATGL和脂肪吞噬/FA流出之间的生理调节和相互作用; 2）定义 ATGL与SIRT 1信号传导和脂肪吞噬诱导的联系机制;以及3）阐明ATGL与SIRT 1信号传导和脂肪吞噬诱导的调节， 溶酶体介导的FA外排对肝脏能量代谢的影响。目的1将采用细胞，灌注 肝脏和小鼠模型来表征生理因素如何调节脂肪吞噬。目标2将使用两个单元格 和小鼠模型来剖析ATGL与自噬/脂肪吞噬调节之间的信号网络 和FA流出。目的3将集中在溶酶体融合到质膜作为一个治疗靶点，以增加 脂肪吞噬这些研究是创新的，因为它们将回答有关LD调节的新问题 category和信号。这项工作是有意义的，因为它促进了我们对定义的理解。 这将对实现以下目标产生积极和持续的影响： 预防或治疗NAFLD和相关合并症。