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: 10292442
• 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/10292442
• 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; 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; 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，骨关节炎是最常见的疾病 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，并且近 80% 的退伍军人患有肥胖症 对于退伍军人和其他人，正在开发有效的疾病缓解方法。 骨关节炎的治疗是一个未满足的主要医疗需求。随着骨关节炎的进展，滑膜关节器官经常出现衰竭。 以关节软骨退化为核心疾病特征，软骨细胞是唯一的细胞。 关节透明软骨，负责维持细胞外基质之间的稳态平衡 OA 中软骨细胞的基质合成代谢和分解代谢功能障碍，因局部炎症而加剧。 过程，导致软骨细胞分解代谢活动过度，由一氧化氮等因素引起 (NO)、基质金属蛋白酶 (MMP) 和聚集蛋白聚糖酶可以与某些细胞代谢相交叉。 表观遗传和转录因子修饰介导细胞重编程 ATP 柠檬酸裂解酶 (ACLY)。 是一种代谢酶，可将线粒体产生的柠檬酸转化为细胞质中的乙酰辅酶A， 细胞核，作为细胞质中脂质从头合成和蛋白质乙酰化的乙酰基供体， 以及细胞核中组蛋白和转录因子的乙酰化，从而调节我们的基因表达。 初步研究表明，人类膝关节 OA 软骨细胞/软骨的 ACLY 活性增加， 与 OA 软骨细胞中组蛋白乙酰化的增加有关。 通过调节乙酰化来增加合成代谢并减少炎症介导的分解代谢活动 基于这个翻译项目中的这些发现，我们建议测试我们的组蛋白和转录因子。 我们将测试软骨细胞 ACLY 是体内 OA 的可药物代谢靶点的中心假设。 假设 (1) IL-1β 和 IGF-1 激活 Akt 信号传导，已知这两种物质与 衰老和肥胖，并且在 OA 软骨中上调，导致人类软骨细胞中 ACLY 活性增加； (2) 通过限制 ACLY 活性来实现软骨保护，这是由软骨细胞自噬增加介导的 (3) 抑制 ACLY 活性可保护小鼠免受肥胖引起的 OA 的发生和进展 通过高脂肪饮食（HFD）和年龄相关的自发性OA的体内研究的完成将提供新的内容。 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 发生和进展的新方法，特别是 那些因衰老和/或肥胖而风险增加的人。

项目成果

AMPK Activation by A-769662 Controls IL-6 Expression in Inflammatory Arthritis.

A-769662 激活 AMPK 控制炎症性关节炎中的 IL-6 表达。

• 发表时间: 2015
• 影响因子: 3.7
• 作者: Guma, Monica;Wang, Yun;Viollet, Benoit;Liu
• 通讯作者: Liu

Metformin limits osteoarthritis development and progression through activation of AMPK signalling.

二甲双胍通过激活 AMPK 信号传导来限制骨关节炎的发生和进展。

• 发表时间: 2020
• 影响因子: 27.4
• 作者: Li, Jun;Zhang, Bin;Liu, Wei;Lu, Ke;Pan, Haobo;Wang, Tingyu;Oh, Chun;Yi, Dan;Huang, Jian;Zhao, Lan;Ning, Guangzhi;Xing, Cong;Xiao, Guozhi;Liu;Feng, Shiqing;Chen, Di
• 通讯作者: Chen, Di

Mitochondrial Biogenesis, Activity, and DNA Isolation in Chondrocytes.

软骨细胞中的线粒体生物发生、活性和 DNA 分离。

• DOI: 10.1007/978-1-0716-1119-7_14
• 发表时间: 2021
• 期刊: Methods in molecular biology
• 作者: Yun Wang;Liang‐Yu Chen;Liu
• 通讯作者: Liu

Review: Metabolic Regulation of Inflammation in Osteoarthritis.

评论：骨关节炎炎症的代谢调节。

• 发表时间: 2017
• 作者: Berenbaum, Francis;Griffin, Timothy M;Liu
• 通讯作者: Liu

Cartilage-targeting ultrasmall lipid-polymer hybrid nanoparticles for the prevention of cartilage degradation.

用于预防软骨退化的软骨靶向超小型脂质聚合物混合纳米颗粒。

• 发表时间: 2021-01
• 影响因子: 7.4
• 作者: Ai, Xiangzhao;Duan, Yaou;Zhang, Qiangzhe;Sun, Derrick;Fang, Ronnie H;Liu;Gao, Weiwei;Zhang, Liangfang
• 通讯作者: Zhang, Liangfang