Role of Lipid Phosphatases in Cholesterol and Triglyceride Synthesis

描述（由申请人提供）：心血管和脑血管疾病是全球主要的死亡原因。肥胖、胆固醇和甘油三酯循环水平升高以及循环脂蛋白组成的改变是心血管和脑血管疾病的主要危险因素。肥胖是一种能量平衡失调。当能量输入超过能量输出时，消耗的大部分多余热量转化为甘油三酯并储存在脂肪组织中。类似地，当胆固醇的从头合成和从饮食来源提供胆固醇之间的平衡超过正常胆固醇需求和消除这种必需固醇的能力时，循环胆固醇增加导致胆固醇沉积在脉管系统中。肥胖症及其并发症包括高胆固醇血症的临床管理目前集中在饮食、体力活动和行为的改变上。由于这些策略的有效性有限，肥胖症的患病率继续增加。胆固醇合成的药理学抑制是高胆固醇血症临床管理的主要和目前最有效的策略。尽管迄今为止，致力于开发用于治疗肥胖症的药理学策略，重点是抑制食欲和干扰脂质吸收，取得了一定的成功，但使用小鼠模型的最新进展表明，抑制甘油三酯合成可能是一种可行且有效的治疗策略。因此，鉴定负责甘油三酯和胆固醇合成的途径的组分，并全面了解这些过程是如何调节的，对于开发用于治疗肥胖症和高胆固醇血症的新的或改进的药物至关重要。由于它们在细胞代谢中的关键地位，负责胆固醇和甘油三酯从头合成的途径已被深入研究，但我们的知识仍然存在重大差距。两类脂质磷酸酯，聚类异戊二烯二磷酸和磷脂酸是胆固醇和甘油三酯合成中的关键中间体，但使这些中间体去磷酸化的酶最近才被鉴定。本研究的总体目标是通过研究两种新发现的在类异戊二烯、甾醇和甘油三酯合成中起核心作用的脂质磷酸酶的调节和功能来解决我们知识中的这些空白。我们的研究使用生物化学，细胞和分子生物学技术来研究这些酶在体外和生物医学相关模型细胞系统中的调节和功能。在第一个目标，我们将使用这些方法来测试的假设，一个完整的膜酶称为聚异戊二烯二磷酸磷酸酶是胆固醇合成和蛋白质异戊二烯化的调节剂。在第二个目标的建议，我们将测试的假设，催化甘油三酯合成的关键步骤的磷脂酸磷酸酶的活性是由一种新的膜靶向基序调节。公共卫生相关性：肥胖和胆固醇水平升高是心血管和脑血管疾病的主要危险因素，这些疾病是该国死亡的主要原因。肥胖是一种能量平衡失调。当能量输入超过能量输出时，消耗的大部分多余热量转化为甘油三酯并储存为身体脂肪。类似地，当胆固醇合成和从饮食来源提供胆固醇之间的平衡超过正常胆固醇需求和胆固醇排泄时，循环胆固醇增加。在这个研究项目中，我们将测试有关新发现的酶的调节和功能的具体假设，这些酶在脂肪和胆固醇的合成和代谢中起着核心作用。我们工作的完成将为这些脂质的合成如何调节提供新的见解，这一过程如何在疾病中改变，以及靶向这些过程为肥胖和心血管疾病提供新疗法的可行性。

DESCRIPTION (provided by applicant): Cardiovascular and cerebrovascular diseases are the leading causes of death worldwide. Obesity, elevations in circulating levels of cholesterol and triglycerides and alterations in the composition of circulating lipoproteins are major risk factors for cardiovascular and cerebrovascular disease. Obesity is a disorder of energy balance. When energy input exceeds energy output most of the excess calories consumed are converted to triglycerides and stored in adipose tissue. Similarly, increases in circulating cholesterol leading to cholesterol deposition in the vasculature occur when the balance between de novo synthesis of cholesterol and provision of cholesterol from dietary sources exceeds normal cholesterol requirements and capacity to eliminate this essential sterol. Clinical management of obesity and its complications including hypercholesterolemia presently focuses on modifications of diet, physical activity and behavior. Because these strategies are of limited effectiveness, the prevalence of obesity continues to increase. Pharmacological inhibition of cholesterol synthesis is the primary and presently most effective strategy for the clinical management of hypercholesterolemia. Although to date efforts to develop pharmacological strategies for treatment of obesity focusing on appetite suppression and interference with lipid absorption have met with moderate success, recent advances using mouse models suggest that inhibition of triglyceride synthesis may be a viable and effective treatment strategy. Identification of components of the pathways responsible for synthesis of triglycerides and cholesterol and development of a complete understanding of how these processes are regulated is therefore critical for the development of new or improved agents for treatment of obesity and hypercholesterolemia. Because of their pivotal position in cellular metabolism, the pathways responsible for the de novo synthesis of cholesterol and triglycerides have been intensively studied but significant gaps in our knowledge remain. Two classes of lipid phosphate esters, polyisoprenoid diphosphates and phosphatidic acid are critical intermediates in the synthesis of cholesterol and triglyceride but enzymes that dephosphorylate these intermediates have only recently been identified. The overall goal of this research is to address these gaps in our knowledge by investigating the regulation and function of two newly identified lipid phosphatases that play central roles in the synthesis of isoprenoids, sterols and triglycerides. Our research uses techniques of biochemistry, cell and molecular biology to study the regulation and function of these enzymes in vitro and in biomedically relevant model cell systems. In the first aim we will use these approaches to test the hypothesis that an integral membrane enzyme termed polyisoprenoid diphosphate phosphatase is a regulator of cholesterol synthesis and protein isoprenylation. In the second aim of the proposal we will test the hypothesis that activity of a phosphatidic acid phosphatase enzyme that catalyses a critical step in triglyceride synthesis is regulated by a novel membrane targeting motif. PUBLIC HEALTH RELEVANCE: Obesity and elevated cholesterol levels are major risk factors for Cardiovascular and Cerebrovascular disease which are the leading causes of death in this country. Obesity is a disorder of energy balance. When energy input exceeds energy output most of the excess calories consumed are converted to triglycerides and stored as body fat. Similarly, increases in circulating cholesterol occur when the balance between cholesterol synthesis and provision of cholesterol from dietary sources exceeds normal cholesterol requirements and cholesterol excretion. In this research project we will test specific hypotheses about the regulation and function of newly identified enzymes that play central roles in the synthesis and metabolism of fat and cholesterol. Completion of our work will provide new insights into how synthesis of these lipids is regulated, how this process may be altered in disease and the feasibility of targeting these processes to provide novel therapies for obesity and cardiovascular disease.