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

项目总结 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世界各地的经济和医疗体系构成了重大威胁。 因此，迫切需要新的治疗靶点和策略。脂肪代谢异常， 尤其是在肝脏中，是代谢性疾病的标志，而ATP-柠檬酸裂解酶(ACLY)，它 产生用于脂质和胆固醇合成的乙酰辅酶A，已成为一种有希望的治疗靶点 脂肪肝。到目前为止，几种ACLY抑制剂正在开发中，用于临床，其中一种专门用于 靶向肝脏ACLY已被FDA批准用于治疗高胆固醇。然而，现在人们意识到， 产生脂肪的乙酰辅酶A有多种途径，这些途径依赖于组织和饮食。例如，产生脂肪的 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)从乙酸酯中衍生出来， 新出现的数据表明，可能存在其他生成脂肪的乙酰辅酶A的途径。此外，在最后一步工作 十年的研究已经确凿地表明，人类体内的脂质动态平衡需要身体的 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)，这得到了对小鼠模型的研究的证实，进一步表明棕色脂肪和 肝脏和两个脂肪含量最高的器官。这些发现的含义是，以ACLY为目标 从系统上看，在一种组织或饮食背景下可能是有益的，而在另一种组织或饮食背景下针对它可能是有害的。 事实上，我们公布的和由这笔赠款支持的初步数据表明，在 在棕色和白色脂肪组织和肝脏中的ACLY和ACSS2通路都是上下文(即饮食和 温度)依赖的和补偿的。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机制有更深入的了解 合成了造脂乙酰辅酶A，并在体内应用。 在这份提案中，我们利用在上一个资助期产生的工具和技术来调查 ACLY和ACSS2在生热脂肪细胞(Aim 1)和肝细胞(Aim 2)中的生物学功能我们的 该方法利用了我们已有的ACLY和ACSS2的组织特异性单基因和双基因敲除模型 代谢组学、分室代谢物分析和体内稳定同位素的产生和技术 我们已经适应了对脂肪组织和肝脏的研究。这项工作将由一个 具有互补专业知识的研究人员，他们多年来合作卓有成效。我们的长- 学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.