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.

项目摘要 营养感应途径（mTOR，AMPK，sirtuins）是衰老过程的核心组成部分， 对细胞功能至关重要的翻译后修饰对环境因素的影响。迄今为止，这方面的研究 主要集中在干预措施，如热量或蛋白质的限制，推动寿命或减缓衰老相关的 病态从这些干预研究中衍生出的一个新兴研究领域强调了脂肪的潜力 脂肪酶，即储存在脂滴（LD）中的三酰甘油的脂解降解，是脂肪酶降解过程中的主要因素。 衰老的过程尽管有越来越多的证据表明脂解的有益作用， 脂肪分解对健康的影响知之甚少。Charles Najt博士最近发现了LD蛋白perilipin 5（PLIN 5） 是脂肪分解和营养传感器SIRT 1之间的关键环节; PLIN 5消融脂肪甘油三酯的损失 脂肪酶（ATGL）介导的SIRT 1活化。我们公布的和初步的数据显示， cAMP/PKA信号传导，其由禁食或热量限制（CR）驱动，PLIN 5结合并转运 脂肪分解产生的单不饱和脂肪酸（MUFAs）进入细胞核。一旦进入细胞核， 从PLIN 5变构激活SIRT 1。这些结果提供了一个潜在的机制，解释了不断增长的 将MUFA与改善健康寿命联系起来的文献。然而，当CR或间歇性禁食时， 虽然干预措施显示增加健康寿命，增加PLIN 5表达，但对PLIN 5的直接作用知之甚少。 PLIN 5在健康寿命或寿命方面。一些研究表明，Plin 5的表达在中年左右达到高峰， 随着时间的推移而减少或在代谢疾病期间氧化组织的急剧减少， 这些变化或Plin 5表达降低的影响是未知的。这是一个重大的知识差距 因为PLIN 5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被证实。 建立。在目前的提案中，我们的目标是填补这一知识空白，直接提供重要的结果 将PLIN 5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PLIN 5信号在细胞内表达， 细胞核对于在衰老过程中维持代谢健康至关重要，而这个信号轴的崩溃 导致与年龄相关的疾病，降低健康寿命。此外，我们建议维持PLIN 5 在整个生命过程中，信号，将增加健康寿命和加强饮食干预。这种假设是 重要的是，迄今为止还没有研究确定PLIN 5在衰老过程中的作用或它在健康中的作用 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。通过 我们专注于脂质信号传导中的一个新的利基，并将PLIN 5与健康和寿命直接相关， 强大的基础生物学，与健康老龄化密切相关。拟议的研究是一致的 随着资金领域列为特别感兴趣的老龄化，允许申请人进展到独立的 在一个新的和不断增长的领域的研究者地位。