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

项目摘要 代谢性疾病，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保健系统构成重大威胁。 因此，非常需要新的治疗靶标和策略。脂质代谢异常， 特别是在肝脏中，是代谢疾病的标志，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，已成为一种有前途的治疗靶点， 脂肪肝在这一点上，几种ACLY抑制剂正在开发用于临床应用，其中一种特别适用于 ACLY已被FDA批准用于治疗高胆固醇。然而，现在认识到， 有多种途径产生脂肪生成乙酰辅酶A，这些途径是组织和饮食依赖性的。例如，脂肪生成 乙酰辅酶A也可以在某些饮食环境中通过乙酰辅酶A合成酶2（ACSS 2）从乙酸衍生， 并且新出现的数据表明可能存在另外的脂肪生成乙酰辅酶A的途径。此外，工作在最后 十年来，科学家们已经明确表明，人体内的脂质稳态需要人体内 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），这被进一步表明棕色脂肪和 肝脏和两个最易生脂的器官。这些发现的意义在于， 全身性地在一种组织或饮食环境中可能是有益的，而在另一种组织或饮食环境中靶向它可能是有害的。 事实上，我们公布的和初步的数据支持这项赠款显示，有相当大的相互作用， 在棕色和白色脂肪组织和肝脏中的ACLY和ACSS 2途径， 温度）依赖性和补偿性。因此，有效部署ACLY或ACSS 2抑制剂将需要 更深入地了解组织，饮食和体温调节依赖机制， 在体内合成并利用脂肪生成乙酰辅酶A。 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ACSS 2在产热脂肪细胞（Aim 1）和肝细胞（Aim 2）中的生物学功能。我们 一种方法利用了ACLY和ACSS 2的组织特异性单敲除和双敲除模型，我们已经 代谢组学、区室化代谢物分析和体内稳定同位素技术 这是我们用来研究脂肪组织和肝脏的追踪技术。这项工作将由一个小组协助， 具有互补专业知识的研究人员，多年来进行了富有成效的合作。我们长久以来- 长期目标是确定最佳策略，如药物/饮食联合疗法，以帮助患有 代谢性疾病

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.