ATP-Citrate Lyase As A Novel Metabolic Target for Osteoarthritis

ATP-柠檬酸裂解酶作为骨关节炎的新型代谢靶点

• 批准号: 10045945
• 负责人: RU BRYAN
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10045945
• 关键词: 5' -AMP-activated protein kinase; ATP Citrate (pro-S)-Lyase; Acetyl Coenzyme A; Acetylation; Age; Aging; Anabolism; Anti-Inflammatory Agents; Arthritis; Attenuated; Autophagocytosis; Back; Bioavailable; Bioenergetics; Biosensor; Caloric Restriction; Carbon; Cartilage; Catabolism; Cell Nucleus; Cells; Chondrocytes; Citrates; Citric Acid Cycle; Cyclic AMP-Dependent Protein Kinases; Cytosol; Degenerative polyarthritis; Development; Disease; Energy Metabolism; Enzymes; Epigenetic Process; Equilibrium; Extracellular Matrix; Failure; Fatty Acids; Functional disorder; Garcinia; Gene Expression; Genes; Genetic Transcription; Glucose; Healthcare; High Fat Diet; Histone Acetylation; Human; Hyaline Cartilage; Inflammation; Inflammatory; Insulin Resistance; Insulin-Like Growth Factor I; Interleukin-1 beta; Knee Osteoarthritis; Knockout Mice; Lipids; Lysine; MMP3 gene; Mediating; Medical; Metabolic; Metabolism; Mitochondria; Modeling; Modification; Mus; Nitric Oxide; Nuclear Translocation; Obesity; Oral; Organ; Pharmaceutical Preparations; Pharmacology; Phenotype; Phosphorylation; Process; Production; Protein Acetylation; Protein Kinase; Proteins; Public Health; Quality Control; Recycling; Rest; Risk; Risk Factors; Role; Signal Transduction; Synovial joint; Testing; Therapeutic; Tissues; Veterans; age related; aggrecan; aggrecanase; analog; articular cartilage; cartilage degradation; design; high risk; in vivo; inhibitor/antagonist; insight; mRNA Expression; mimetics; novel; novel strategies; prevent; promoter; therapeutically effective; transcription factor; translational study

Aging and obesity are the major risk factors for development of osteoarthritis (OA), the most common form of arthritis. Veterans are at high risk of developing OA, because over 12.4 millions veterans are age 65 or older, and nearly 80% of veterans are obese. For veterans and others, developing effective disease-modifying therapy for OA is a major unmet medical need. As OA progresses, failure of the synovial joint organ frequently develops, with degeneration of articular cartilage as a core disease feature. Chondrocytes, the sole cells in articular hyaline cartilage, are responsible for maintaining the homeostatic balance between extracellular matrix anabolism and catabolism. Dysfunction of chondrocytes in OA, amplified by local inflammatory processes, leads to an excess of chondrocyte catabolic activity, medicated by factors including nitric oxide (NO), matrix metalloproteinasess (MMPs) and aggrecanases. Cellular metabolism can intersect with certain epigenetic and transcription factor modifications to mediate cellular re-programming. ATP citrate lyase (ACLY) is a metabolic enzyme that converts citrate generated from mitochondria to acetyl-CoA in the cytosol and nucleus, which serves as an acetyl donor for de novo lipid synthesis and acetylation of proteins in the cytosol, and acetylation of histones and transcription factors in the nucleus, thereby modulating gene expression. Our preliminary studies reveal that human knee OA chondrocytes/cartilages have increased ACLY activity, associated with increased acetylation of histones. Pharmacologic inhibition of ACLY in OA chondrocytes increases anabolic and decreases inflammation-mediated catabolic activities through modulating acetylation of histones and transcription factors. Building on these findings in this translational project, we propose to test our central hypothesis that chondrocyte ACLY is a druggable metabolic target for OA in vivo. We will test hypotheses that (1) activation of Akt signaling by IL-1β and IGF-1, both of which are known to associate with aging and obesity and are upregulated in OA cartilage, drives increased ACLY activity in human chondrocytes; (2) Chondroprotection by limiting ACLY activity is mediated by increased chondrocyte autophagy; (3) Suppression of ACLY activity protects mice from OA development and progression in both obesity-induced OA via high-fat diet (HFD) and age-related spontaneous OA in vivo. Completion of these studies will provide new insights into how metabolic alterations modulated by ACLY influence cartilage tissue integrity, and may provide a novel approach by limiting ACLY activity to suppress or delay OA development and progression, particularly in those at increased risk due to aging and/or obesity.

衰老和肥胖是骨关节炎（OA）发展的主要危险因素， 关节炎的症状退伍军人患OA的风险很高，因为超过1240万退伍军人年龄在65岁或以上。 年龄较大，近80%的退伍军人肥胖。对于退伍军人和其他人来说，开发有效的疾病修饰 OA的治疗是一个主要的未满足的医疗需求。随着OA的进展，滑膜关节器官的衰竭经常发生， 发展，关节软骨退行性变是核心疾病特征。软骨细胞， 关节透明软骨，负责维持细胞外基质和细胞外基质之间的稳态平衡。 基质吸附剂和催化剂。OA中软骨细胞的功能障碍，由局部炎症放大 过程，导致软骨细胞分解代谢活性过剩，由包括一氧化氮在内的因子提供药物 (NO)、基质金属蛋白酶（MMPs）和聚集蛋白聚糖酶。细胞代谢可以与某些 表观遗传和转录因子修饰以介导细胞重编程。三磷酸腺苷柠檬酸裂解酶 是一种代谢酶，可将线粒体产生的柠檬酸盐转化为细胞溶质中的乙酰辅酶A， 细胞核，其作为乙酰供体用于从头脂质合成和胞质溶胶中蛋白质的乙酰化， 以及细胞核中组蛋白和转录因子的乙酰化，从而调节基因表达。我们 初步研究揭示人膝OA软骨细胞/软骨具有增加的ACLY活性， 与组蛋白乙酰化增加有关。ACLY在OA软骨细胞中的药理学抑制 增加合成代谢和减少炎症介导的分解代谢活动，通过调节乙酰化 组蛋白和转录因子。在这个翻译项目的这些发现的基础上，我们建议测试我们的 中心假设，软骨细胞ACLY是体内OA的药物代谢靶点。我们将测试 假设（1）IL-1 β和IGF-1激活Akt信号传导，已知这两种物质与 衰老和肥胖，并在OA软骨中上调，驱动人软骨细胞中ACLY活性增加; (2)通过限制ACLY活性的软骨保护作用是由软骨细胞自噬增加介导的;（3） ACLY活性的抑制可保护小鼠免受肥胖诱导的OA的发展和进展。 通过高脂饮食（HFD）和体内年龄相关的自发性OA。这些研究的完成将提供新的 深入了解ACLY调节的代谢改变如何影响软骨组织完整性，并可能提供 一种通过限制ACLY活性来抑制或延迟OA发展和进展的新方法，特别是 对于那些因衰老和/或肥胖而风险增加的人。