Functional studies of PGRMC1 in cholesterol homeostasis

PGRMC1 在胆固醇稳态中的功能研究

• 批准号: 7898673
• 负责人: PETER J. ESPENSHADE
• 金额: $ 20.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7898673
• 关键词: Adenoviruses; Adult; Affinity; American; Animals; Atherosclerosis; Bile Acid Biosynthesis Pathway; Bile Acids; Binding; Biology; Blood; Cardiovascular Diseases; Catabolism; Cells; Cellular Membrane; Cholesterol; Cholesterol Homeostasis; Complex; Cultured Cells; Cytochrome P450; Cytochromes; Detergents; Dietary intake; Electrons; Enzymes; Excretory function; Goals; Health; Heart Diseases; Hepatocyte; Human; Immune Sera; Lead; Liver; Mass Spectrum Analysis; Mediating; Mouse Protein; Mus; Play; Property; Proteins; RNA Interference; Regulation; Role; Serum; Steroids; Testing; Therapeutic; Work; Yeasts; base; drug metabolism; embryonic stem cell; enzyme activity; heme-binding protein; high risk; improved; in vivo; novel; prevent; protein complex; public health relevance; research study

DESCRIPTION (provided by applicant): Cholesterol is a fundamental component of cellular membranes and plays a crucial role in regulating their structural properties. In addition, cholesterol serves as a precursor for important compounds, such as bile acids, steroids, and oxysterols. Although essential, elevated serum cholesterol is associated with heart disease and atherosclerosis. Notably, more than 38 million American adults have a total blood cholesterol e 240 mg/dL, which is considered high risk for cardiovascular disease. For these reasons, understanding how to maintain low, but sufficient, serum cholesterol levels is critical for human health. Cholesterol supply is controlled by multiple factors: dietary intake, synthesis, storage, catabolism and excretion. Cytochrome P450 monoxygenases play a key role in regulating cholesterol homeostasis through their functions in cholesterol, oxysterol, bile acid and steroid synthesis. Recently, we identified the heme-binding protein PGRMC1 as a binding partner and positive regulator of the cytochrome P450 Cyp51A1 in cholesterol synthesis. Using transfected cultured cells, we found that PGRMC1 binds tightly to a diverse set of P450 enzymes, including Cyp3A4, Cyp21A2 and Cyp7A1 that function in drug metabolism, steroid and bile acid synthesis, respectively. Based on these findings, we hypothesize that PGRMC1 is an important regulator of cholesterol homeostasis in animals. As a first step, we propose the following aims to test whether PGRMC1 is required for cholesterol homeostasis in mouse liver through regulation of Cyp51A1 and other P450 enzymes. AIM 1. To determine the function of PGRMC1 in liver cholesterol synthesis. AIM 2. To identify PGRMC1-interacting proteins from mouse liver. These experiments are a first step toward our long-term goal of understanding the function of PGRMC1 in systemic cholesterol homeostasis. The central role that cytochrome P450 enzymes play in regulation of serum cholesterol suggests that a clear understanding of PGRMC1 function will lead to improved therapeutic strategies for lowering serum cholesterol and preventing heart disease. PUBLIC HEALTH RELEVANCE: More than 38 million American adults have a total blood cholesterol e 240 mg/dL, which is considered high risk for cardiovascular disease. In this project, we will determine the function of the novel cytochrome P450 regulator PGRMC1 in systemic cholesterol homeostasis. The central role that cytochrome P450 enzymes play in regulation of serum cholesterol suggests that a clear understanding of PGRMC1 function will lead to improved therapeutic strategies for lowering serum cholesterol and preventing heart disease.

说明(申请人提供)：胆固醇是细胞膜的基本成分，在调节其结构特性方面起着至关重要的作用。此外，胆固醇也是重要化合物的前体，如胆汁酸、类固醇和氧化类固醇。虽然血清胆固醇升高是必要的，但它与心脏病和动脉粥样硬化有关。值得注意的是，超过3800万美国成年人的血液总胆固醇水平为240毫克/分升，这被认为是心血管疾病的高风险。出于这些原因，了解如何保持较低但足够的血清胆固醇水平对人类健康至关重要。胆固醇的供应受多种因素控制：饮食摄入、合成、储存、分解代谢和排泄。细胞色素P450单加氧酶通过其在胆固醇、氧固醇、胆汁酸和类固醇合成中的作用，在调节胆固醇的动态平衡中起着关键作用。最近，我们发现血红素结合蛋白PGRMC1是细胞色素P450 Cyp51A1在胆固醇合成中的结合伙伴和正调节因子。利用转基因培养细胞，我们发现PGRMC1与一系列不同的P450酶紧密结合，包括分别在药物代谢、类固醇和胆汁酸合成中发挥作用的CYP3A4、CYP21A2和Cyp7A1。基于这些发现，我们假设PGRMC1是动物体内胆固醇稳态的重要调节因子。作为第一步，我们建议以下目的是通过调节Cyp51A1和其他P450酶来测试PGRMC1是否对小鼠肝脏的胆固醇稳态是必需的。目的1.研究PGRMC1在肝脏胆固醇合成中的作用。目的2.从小鼠肝脏中鉴定PGRMC1相互作用蛋白。这些实验是我们朝着了解PGRMC1在全身胆固醇稳态中的功能的长期目标迈出的第一步。细胞色素P450酶在调节血清胆固醇中的核心作用表明，对PGRMC1功能的清楚了解将有助于改进降低血清胆固醇和预防心脏病的治疗策略。与公共健康相关：超过3800万美国成年人的血液总胆固醇水平为240毫克/分升，这被认为是心血管疾病的高风险。在这个项目中，我们将确定新的细胞色素P450调节因子PGRMC1在系统胆固醇动态平衡中的作用。细胞色素P450酶在调节血清胆固醇中的核心作用表明，对PGRMC1功能的清楚了解将有助于改进降低血清胆固醇和预防心脏病的治疗策略。