Perilipin 5: Linking lipid droplets to nutrient sensing and healthy aging

Perilipin 5：将脂滴与营养传感和健康衰老联系起来

• 批准号: 10362618
• 负责人: Charles P Najt
• 金额: $ 10.26万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10362618
• 关键词: Adipose tissue; Aging; Animal Model; Area; Autophagocytosis; Binding; Biogenesis; Biology; Biotin; Caloric Restriction; Catabolism; Cell Nucleus; Cell Respiration; Cell physiology; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Couples; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Deacetylase; Development; Diet; Dietary Factors; Dietary Intervention; Environmental Risk Factor; FRAP1 gene; Fasting; Fatty Acids; Fatty acid glycerol esters; Funding; Goals; Health; Health Benefit; Inflammation; Intermittent fasting; Intervention; Intervention Studies; Knock-out; Knowledge; Life; Ligase; Link; Lipase; Lipids; Lipolysis; Literature; Longevity; Maps; Mediating; Mediterranean Diet; Metabolic; Metabolic Diseases; Metabolic dysfunction; Mitochondria; Modification; Monounsaturated Fatty Acids; Morbidity - disease rate; Mus; Nuclear; Nutrient; Olive oil preparation; Pathway interactions; Physiological; Process; Proteins; Publishing; Research; Research Personnel; Role; SIRT1 gene; Signal Transduction; Sirtuins; Supplementation; Surface; Testing; Time; Tissues; Translations; Triglycerides; Work; age related; detection of nutrient; dietary; epidemiology study; flexibility; good diet; healthspan; healthy aging; improved; interest; lipid metabolism; lipid transport; middle age; novel; overexpression; perilipin; protective effect; response; sensor

PROJECT SUMMARY Nutrient sensing pathways (mTOR, AMPK, sirtuins) are core components underlying the aging process, linking post-translation modifications critical to cellular function to environmental factors. To date, research in this area has largely focused on interventions such as caloric or protein restriction that drive lifespan or slow aging-related morbidities. An emerging area of research derived from these intervention studies highlights the potential of fat catabolism, the lipolytic degradation of triacylglycerol stored within lipid droplets (LDs), as a major factor during the aging process. Despite accumulating evidence for a beneficial role of lipolysis, the mechanism that links lipolysis to healthspan is poorly understood. Dr. Charles Najt recently identified the LD protein perilipin 5 (PLIN5) to be the critical link between lipolysis and the nutrient sensor SIRT1; loss of PLIN5 ablated adipose-triglyceride lipase (ATGL)-mediated activation of SIRT1. Our published and preliminary data show that in response to cAMP/PKA signaling, which is driven by fasting or caloric restriction (CR), PLIN5 binds and transports monounsaturated FAs (MUFAs) produced from lipolysis to the nucleus. Once in the nucleus, MUFAs liberated from PLIN5 allosterically activate SIRT1. These results provide an underlying mechanism explaining the growing body of literature that has linked MUFAs to improved healthspan. Yet, while CR or intermittent fasting, interventions shown to increase healthspan, increase PLIN5 expression, little is known about the direct role of PLIN5 in healthspan or longevity. A few studies indicate Plin5 expression peaks around middle age, slowly decreasing over time or drastically decreases in oxidative tissues during metabolic disease, yet the cause of these changes or the impact of decreased Plin5 expression is unknown. This is a significant gap in knowledge as PLIN5 has been shown to mitigate metabolic disease but its ability to influence health or lifespan has yet to be established. In the current proposal we aim to fill this gap in knowledge, providing significant results directly linking PLIN5 lipid signaling and metabolic flexibility to healthy aging. We hypothesize that PLIN5 signaling in the nucleus is critical for maintaining metabolic health during aging, whereas breakdown of this signaling axis results in age-related morbidities, decreasing healthspan. Moreover, we propose that maintaining PLIN5 signaling throughout life, will increase healthspan and enhance dietary interventions. This hypothesis is significant as no study to date has determined the role of PLIN5 during aging or what role it has in healthspan promoting interventions such as the Mediterranean Diet, which is considered the ideal diet for healthy aging. By focusing on a novel niche in lipid signaling and directly relating PLIN5 to health and lifespan, we are establishing strong fundamental biology that is extremely relevant to healthy aging. The proposed studies are well-aligned with the funding areas listed as of special interest in aging, allowing the applicant to progress to independent investigator status in a new and growing field.

项目概要 营养传感途径（mTOR、AMPK、sirtuins）是衰老过程的核心组成部分，将 对细胞功能和环境因素至关重要的翻译后修饰。迄今为止，该领域的研究 主要关注热量或蛋白质限制等干预措施，以延长寿命或延缓衰老相关 发病率。这些干预研究衍生出的一个新兴研究领域强调了脂肪的潜力 分解代谢，即储存在脂滴 (LD) 内的三酰甘油的脂解降解，是分解代谢过程中的一个主要因素。 老化过程。尽管越来越多的证据表明脂肪分解的有益作用，但链接的机制 人们对脂肪分解对健康寿命的影响知之甚少。 Charles Najt 博士最近发现了 LD 蛋白 perilipin 5 (PLIN5) 成为脂肪分解和营养传感器 SIRT1 之间的关键环节； PLIN5 缺失消除脂肪甘油三酯 脂肪酶 (ATGL) 介导的 SIRT1 激活。我们公布的初步数据表明，为了响应 cAMP/PKA 信号传导由禁食或热量限制 (CR) 驱动，PLIN5 结合并转运 单不饱和脂肪酸 (MUFA) 由脂肪分解至细胞核产生。一旦进入细胞核，MUFA 就会被释放 PLIN5 变构激活 SIRT1。这些结果提供了解释增长的基本机制 大量文献将 MUFA 与延长健康寿命联系起来。然而，当 CR 或间歇性禁食时， 干预措施显示可延长健康寿命、增加 PLIN5 表达，但对其直接作用知之甚少 PLIN5 的健康寿命或寿命。一些研究表明 Plin5 表达在中年左右达到峰值，缓慢 随着时间的推移而减少或在代谢疾病期间氧化组织急剧减少，但其原因 这些变化或 Plin5 表达减少的影响尚不清楚。这是一个巨大的知识差距 因为 PLIN5 已被证明可以减轻代谢疾病，但其影响健康或寿命的能力尚未得到证实。 被成立。在当前的提案中，我们的目标是填补这一知识空白，直接提供显着的成果 将 PLIN5 脂质信号传导和代谢灵活性与健康衰老联系起来。我们假设 PLIN5 信号传导 细胞核对于衰老过程中维持代谢健康至关重要，而该信号轴的崩溃 导致与年龄相关的疾病，缩短健康寿命。此外，我们建议维持 PLIN5 贯穿一生的信号将延长健康寿命并加强饮食干预。这个假设是 意义重大，因为迄今为止还没有研究确定 PLIN5 在衰老过程中的作用或它在健康寿命中的作用 促进地中​​海饮食等干预措施，地中海饮食被认为是健康老龄化的理想饮食。经过 专注于脂质信号转导的新利基并将 PLIN5 与健康和寿命直接相关，我们正在建立 与健康老龄化极其相关的强大的基础生物学。拟议的研究是一致的 资助领域被列为对老龄化特别感兴趣，允许申请人进步到独立 在一个新的、不断发展的领域中的研究者地位。