Role of Lipid Phosphatases in Cholesterol and Triglyceride Synthesis

脂质磷酸酶在胆固醇和甘油三酯合成中的作用

基本信息

批准号：
8059053
负责人：
ANDREW J MORRIS
金额：
$ 9.96万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-15 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8059053
关键词：
1,2-diacylglycerol Address Adipose tissue Amplifiers Anabolism Basic Science Behavior Binding Biochemical Biochemistry Biological Biological Assay Body fat Calories Cardiovascular Diseases Cardiovascular system Cause of Death Cell Nucleus Cell model Cells Cerebrovascular Disorders Cholesterol Cholesterol Synthesis Inhibition Clinical Management Country Data Deposition Desire for food Detergents Development Diet Diet Modification Dietary Cholesterol Diglycerides Diphosphates Disease Drug Delivery Systems Effectiveness Endoplasmic Reticulum Enzymatic Biochemistry Enzymes Equilibrium Excretory function Exhibits Farnesol Funding Gene Family Genes Genetic Glycerophospholipids Goals In Vitro Intervention Intracellular Membranes Isoprenoid Phosphates Knowledge Lecithin Lipids Lipoproteins Malignant Neoplasms Mediating Membrane Membrane Lipids Membrane Proteins Metabolic Metabolic Diseases Metabolism Molecular Molecular and Cellular Biology Mono-S Morbidity - disease rate Nuclear Envelope Obesity Output Pathway interactions Peripheral Pharmaceutical Preparations Phosphatidate Phosphatase Phosphatidic Acid Phospholipids Phosphoric Monoester Hydrolases Physical activity Play Positioning Attribute Prevalence Process Protein Isoforms Protein Isoprenylation Proteins Regulation Research Research Project Grants Role Signal Transduction Source Specific qualifier value Sphingolipids Sterols System Techniques Testing Triglycerides Viral Vector Work Yeasts absorption base cardiovascular risk factor effective therapy energy balance enzyme activity enzyme pathway geranylgeraniol human disease hypercholesterolemia improved inorganic phosphate insight isoprenoid lipid metabolism lipine meetings member membrane model mevalonate mortality mouse model novel obesity management obesity treatment phosphate ester preference programs prospective public health relevance success therapeutic target treatment strategy

项目摘要

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.

描述（由申请人提供）：心血管和脑血管疾病是全球死亡的主要原因。肥胖，胆固醇和甘油三酸酯循环水平的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的障碍。当能量输入超过能量输出时，消耗的大多数过量卡路里都会转化为甘油三酸酯，并存储在脂肪组织中。同样，当胆固醇从头合成与饮食来源提供胆固醇之间的平衡时，循环胆固醇的增加导致脉管系统中的胆固醇沉积会超过正常的胆固醇需求，并且能够消除这种必需的固醇。肥胖症及其并发症（包括高胆固醇血症）目前的临床管理重点是饮食，体育锻炼和行为的修饰。由于这些策略的有效性有限，因此肥胖症的流行率不断增加。胆固醇合成的药理抑制作用是高胆固醇血症临床管理的主要且目前最有效的策略。尽管迄今为止，迄今为止为肥胖症治疗的药理策略的努力而着重于食欲抑制和干扰脂质吸收，但使用小鼠模型的最新进展表明，抑制甘油三酸酯合成的抑制可能是可行有效的治疗策略。因此，鉴定负责合成甘油三酸酯和胆固醇的途径的组成部分，以及对这些过程如何调节的完整理解，因此对于开发新或改进的药物以治疗肥胖和高胆固醇血症的途径至关重要。由于它们在细胞代谢中的关键位置，因此对胆固醇和甘油三酸酯从头合成的途径进行了深入研究，但我们的知识中仍然存在很大的差距。两类脂质磷酸酯，聚异型二磷酸盐和磷脂酸是胆固醇和甘油三酸酯合成的关键中间体，但是最近才鉴定出使这些中间体去磷酸化的酶。这项研究的总体目的是通过研究两种新鉴定的脂质磷酸酶的调节和功能来解决我们的知识中的这些差距，这些脂质磷酸酶在类异型，固醇和甘油三酸酯的合成中起着核心作用。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的模型细胞系统中的调节和功能。在第一个目的中，我们将使用这些方法来检验以下假设：总膜酶称为聚异型二磷酸磷酸磷酸酶是胆固醇合成和蛋白质异on基化的调节剂。在该提案的第二个目的中，我们将检验以下假设：磷脂型磷酸酶的活性会催化甘油三酸酯合成的关键步骤，受到新型膜靶标的调节。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，这是该国的主要死亡原因。肥胖是一种能量平衡的障碍。当能量输入超过能量输出时，消耗的大多数过量卡路里被转化为甘油三酸酯并将其储存为体内脂肪。同样，当胆固醇合成与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，循环胆固醇的增加发生。在该研究项目中，我们将测试有关新确定的酶的调节和功能的特定假设，这些酶在脂肪和胆固醇的合成和代谢中起着核心作用。我们工作的完成将提供有关如何调节这些脂质合成的新见解，如何改变疾病的过程以及针对这些过程的可行性，以为肥胖和心血管疾病提供新的疗法。