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，链接 对环境因素至关重要的翻译后修饰。迄今为止，该领域的研究 主要集中于驱动寿命或与衰老相关的缓慢的热量或蛋白质限制等干预措施 病态。这些干预研究得出的研究领域突出了脂肪的潜力 分解代谢，储存在脂质液滴（LDS）中的三酰基甘油的脂溶性降解，作为过程中的主要因素 衰老过程。尽管积累了证据表明脂解的有益作用，但这种机制是连接的 脂解针对健康范围知之甚少。 Charles Najt博士最近确定了LD蛋白Peripin 5（PLIN5） 成为脂解和营养传感器SIRT1之间的关键联系； PLIN5消融脂肪 - 甘油三酸酯的损失 脂肪酶（ATGL）介导的SIRT1激活。我们发布的初步数据显示， 由禁食或热量限制（CR）驱动的CAMP/PKA信号传导，PLIN5绑定和运输 从脂解到细胞核产生的单不饱和FAS（MUFA）。一旦进入细胞核，Mufas就解放了 从PLIN5变构激活SIRT1。这些结果提供了一种基本机制，解释了增长 文学机构已将MUFA与改进的健康范围联系起来。然而，虽然CR或间歇性禁食，但 显示出可以增加健康状态，增加PLIN5表达的干预措施，对直接作用知之甚少 PLIN5在HealthSpan或longevity中。一些研究表明PLIN5表达在中年左右峰值，缓慢 代谢性疾病期间，随着时间的流逝会减少或大幅减少氧化组织 这些变化或降低PLIN5表达的影响尚不清楚。这是知识的重大差距 由于已显示PLIN5可以减轻代谢疾病，但其影响健康或寿命的能力尚未 建立。在当前的建议中，我们旨在填补这一知识的空白，直接提供重大结果 将PLIN5脂质信号传导和代谢柔韧性与健康衰老联系起来。我们假设PLIN5在 核对于在衰老期间保持代谢健康至关重要，而该信号轴的分解 导致与年龄相关的病态，减少健康状态。此外，我们建议维护PLIN5 一生的信号将增加健康状况并增强饮食干预措施。这个假设是 重要的是迄今为止尚无研究确定PLIN5在衰老中的作用或它在HealthSpan中的作用 促进干预措施，例如地中海饮食，这被认为是健康衰老的理想饮食。经过 侧重于脂质信号传导中的新颖利基，将PLIN5直接与健康和寿命有关，我们正在建立 强大的基本生物学与健康衰老非常相关。拟议的研究很好 由于融资领域在衰老方面特别感兴趣，使申请人可以独立发展 调查员在一个新的和成长的领域的地位。