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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要代谢疾病，包括非酒精性脂肪肝 (NAFLD)、2 型糖尿病和心血管疾病与肥胖有关的疾病对全世界的经济和医疗保健系统构成重大威胁。因此，非常需要新的脂质代谢异常治疗靶点和策略。尤其是在肝脏中，是代谢疾病的一个标志，而 ATP-柠檬酸裂解酶 (ACLY) 产生用于脂质和胆固醇合成的乙酰辅酶A，已成为抗击癌症的有前途的治疗靶点到目前为止，几种 ACLY 抑制剂正在开发用于临床，其中一种是专门针对脂肪肝的。靶向肝脏 ACLY 已被 FDA 批准用于治疗高胆固醇。乙酰辅酶 A 的脂肪生成途径有多种，且与组织和饮食有关，例如，脂肪生成。在某些饮食环境中，乙酰辅酶 A 也可以通过乙酰辅酶 A 合成酶 2 (ACSS2) 从乙酸衍生而来，而且新出现的数据表明可能存在其他的脂肪生成乙酰辅酶A途径。十年来结论性地表明，人类的脂质稳态需要身体的协调热调节器官（棕色脂肪组织）及其能量储存和分配中心（肝脏和白色脂肪组织），这一点得到了小鼠模型研究的证实，进一步表明棕色脂肪和这些发现的意义在于针对 ACLY。全身性地在一种组织或饮食环境中可能是有益的，而针对另一种组织或饮食环境可能是有害的。事实上，我们已公布的和由这笔赠款支持的初步数据表明，两者之间存在相当大的相互作用棕色和白色脂肪组织和肝脏中的 ACLY 和 ACSS2 通路都是背景（即饮食和因此，有效地部署 ACLY 或 ACSS2 抑制剂将需要对组织、饮食和体温调节依赖性机制有更深入的了解脂肪生成乙酰辅酶A在体内合成和利用。在本提案中，我们利用上一个资助期产生的工具和技术来调查 ACLY 和 ACSS2 在产热脂肪细胞（目标 1）和肝细胞（目标 2）中的生物学功能。方法利用我们拥有的 ACLY 和 ACSS2 的组织特异性单敲除和双敲除模型生成的代谢组学技术、区室化代谢物分析和体内稳定同位素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来推动。我们的研究人员具有互补的专业知识，并且多年来一直富有成效地合作。长期目标是确定最佳策略，例如药物/饮食联合疗法，以帮助患有以下疾病的患者代谢性疾病。