Role of acetyl-CoA metabolism in the response to dietary and thermal stress

乙酰辅酶A代谢在饮食和热应激反应中的作用

• 批准号: 10909411
• 负责人: David A Guertin
• 金额: $ 26.31万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-06 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10909411
• 关键词: ATP Citrate (pro-S)-Lyase; Acetate-CoA Ligase; Acetates; Acetyl Coenzyme A; Acetylcarnitine; Acute; Adipocytes; Adipose tissue; Affect; Biochemical; Biological Process; Brown Fat; Carbohydrates; Cardiovascular Diseases; Cholesterol; Citrates; Clinic; Clinical; Collaborations; Combined Modality Therapy; Communication; Compensation; Consumption; Cues; Data; Dependence; Diet; Dietary Cholesterol; Dietary Fats; Economic Burden; Economics; Environment; Enzymes; Exhibits; FDA approved; Fatty Acids; Fatty Liver; Fructose; Funding; Gene Expression Regulation; Genes; Genetic Transcription; Glucose; Goals; Grant; Health; Healthcare Systems; Hepatic; Hepatocyte; Homeostasis; Human; Impairment; Intervention; Isotopes; Knock-out; Link; Lipids; Liver; Metabolic; Metabolic Diseases; Metabolism; Methods; Mitochondria; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nutritional; Obesity; Organ; Outcome; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Play; Population; Productivity; Publishing; Regulation; Research Personnel; Respiration; Role; Route; Source; Techniques; Temperature; Testing; Thermogenesis; Tissues; Update; Weaning; Work; carbohydrate metabolism; clinical development; dietary; forging; gut microbiota; human data; in vivo; inhibitor; lipid biosynthesis; lipid metabolism; metabolomics; mevalonate; mouse model; new therapeutic target; non-alcoholic fatty liver disease; novel therapeutics; pharmacologic; preservation; programs; response; sex; stable isotope; therapeutic target; thermal stress; tool

PROJECT SUMMARY Metabolic diseases including non-alcoholic fatty liver disease (NAFLD), type 2 diabetes, and cardiovascular disease, which are linked to obesity, pose a major threat to economic and healthcare systems worldwide. Accordingly, there is a great need for new therapeutic targets and strategies. Abnormal lipid metabolism, especially in the liver, is a hallmark of metabolic disease, and the enzyme ATP-citrate lyase (ACLY), which generates acetyl-CoA for lipid and cholesterol synthesis, has emerged as a promising therapeutic target against fatty liver. To this point, several ACLY inhibitors are in development for clinical use, and one that specifically targets hepatic ACLY has been FDA approved against high cholesterol. However, it is now appreciated that there are multiple routes to lipogenic acetyl-CoA that are tissue and diet dependent. For example, lipogenic acetyl-CoA can also be derived from acetate via acetyl-CoA synthetase 2 (ACSS2) in certain dietary contexts, and emerging data indicates additional pathways to lipogenic acetyl-CoA likely exist. Moreover, work in the last decade has conclusively shown that lipid homeostasis in humans requires coordination between the body’s thermal regulatory organs (brown adipose tissue) and its energy storing and distribution centers (the liver and white adipose tissue), which is corroborated by studies in murine models further indicating that brown fat and liver and the two most lipogenic organs. The implications of these discoveries are that targeting ACLY systemically in one tissue or dietary context may be beneficial while targeting it in another may be detrimental. Indeed, our published and preliminary data supported by this grant show there is considerable interplay between the ACLY and ACSS2 pathways in brown and white adipose tissues and liver that is both context (i.e. diet and temperature) dependent and compensatory. Thus, effectively deploying ACLY or ACSS2 inhibitors will require a much deeper understanding of the tissue, diet, and thermoregulatory dependent mechanisms by which lipogenic acetyl-CoA is synthesized and utilized in vivo. In this proposal, we leverage tools and techniques generated in the previous funding period to investigate the biological functions of ACLY and ACSS2 in thermogenic adipocytes (Aim 1) and hepatocytes (Aim 2). Our approach utilizes tissue-specific single and double knockout models of ACLY and ACSS2 that we have generated, and techniques in metabolomics, compartmentalized metabolite analysis, and in vivo stable isotope tracing that we have adapted for studying adipose tissues and liver. This work will be facilitated by a team of researchers with complementary expertise and who have collaborated productively for several years. Our long- term goal is to identify optimal strategies, such as drug/diet combination therapies, to help patients suffering from metabolic diseases.

项目摘要 代谢疾病，包括非酒精性脂肪肝病（NAFLD），2型糖尿病和心血管疾病 与肥胖有关的疾病对全球经济和医疗系统构成了重大威胁。 彼此之间，需要新的治疗靶标和策略。异常脂质代谢， 尤其是在肝脏中，是代谢疾病的标志，而酶ATP-CITRATE裂解酶（ACLY），它 生成用于脂质和胆固醇合成的乙酰辅酶A已成为有前途的治疗靶标 脂肪肝。至此，正在开发几种ACLY抑制剂以供临床使用，一种特别是 靶标肝酸ACLY已被FDA批准针对高胆固醇。但是，现在感谢 有多种脂肪生成乙酰辅酶A的途径是组织和饮食依赖性的。例如，脂肪生成 在某些饮食中 并且新兴数据表明可能存在脂肪生成乙酰辅酶A的其他途径。而且，最后工作 十年最终表明，人类的脂质体内稳态需要在人体之间进行协调 热调节器官（棕色脂肪组织）及其能量存储和分配中心（肝脏和 白色脂肪组织），这是通过鼠模型中的研究证实的，进一步表明棕色脂肪和 肝脏和两个最脂的器官。这些发现的含义是针对Acly 在一个组织或饮食环境中，在一个组织或饮食环境中，将其靶向另一个组织可能是有益的。 确实，我们已发布和初步的数据得到了这笔赠款的支持，这表明 棕色和白色脂肪组织和肝脏中的ACLY和ACSS2途径既是背景（即饮食和饮食） 温度）依赖和代偿性。那，有效部署ACLY或ACSS2抑制剂将需要 对组织，饮食和调节依赖性机制的更深入了解 脂肪生成乙酰辅酶A在体内合成和使用。 在此提案中，我们利用上一个资金期间生成的工具和技术来调查 ACLY和ACS2在热脂肪细胞（AIM 1）和肝细胞（AIM 2）中的生物学功能。我们的 方法利用组织特异性的单敲门和双敲除模型的ACLY和ACSS2我们拥有的 产生的和代谢组学，分隔代谢物分析和体内稳定同位素的技术 追踪我们已经适应研究脂肪组织和肝脏。这项工作将由一个团队组成 具有完善专业知识的研究人员，并且有效地合作了几年。我们的长期 术语目标是确定最佳策略，例如药物/饮食组合疗法，以帮助患者患者 代谢疾病。