The role of PGRMC1 in hepatic cholesterol homeostasis

PGRMC1 在肝脏胆固醇稳态中的作用

• 批准号: 8060758
• 负责人: Rita Thomas Brookheart
• 金额: $ 4.84万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8060758
• 关键词: Adult; Affect; Bile Acids; Binding; Cardiovascular Diseases; Cells; Cellular Membrane; Cholesterol; Cholesterol Homeostasis; Cytochrome P450; Development; Dietary intake; Embryo; Enzymes; Excretory function; Heme; Hepatic; Human; Hydroxymethylglutaryl-CoA reductase; Investigation; Kidney; Knowledge; Lanosterol; Lead; Lipids; Lipoproteins; Liver; Membrane Proteins; Metabolism; Mixed Function Oxygenases; Organ; Pharmaceutical Preparations; Prevalence; Preventive; Role; Serum; Signal Transduction; Steroids; Structure; Testing; Therapeutic; base; cardiovascular disorder risk; fluidity; heme-binding protein; novel; novel strategies; novel therapeutic intervention; particle; prevent; small hairpin RNA; sterol homeostasis

DESCRIPTION (provided by applicant): Cholesterol is essential for the proper structure and fluidity of cellular membranes and for the function of membrane proteins. Cholesterol also serves as a precursor of steroids, oxysterols, and bile acids. These metabolites serve important functions in signal transduction and, in the case of bile acids, lipid solubilization. Elevated serum cholesterol levels are associated with increased risk for cardiovascular disease (CVD). A clear understanding of how cells regulate cholesterol synthesis will accelerate the development of novel preventive and therapeutic approaches to CVD. In humans, the supply of cholesterol in the body is controlled by several factors including dietary intake, synthesis, storage, and excretion. Key regulators of cholesterol synthesis and metabolism are the cytochrome P450 monooxygenases. The synthesis of cholesterol from lanosterol requires the P450 enzyme, Cyp51A1. Our lab recently identified the heme-binding protein PGRMC1 as a binding partner and positive regulator of Cyp51A1 and demonstrated that shRNA knockdown of PGRMC1 in human embryonic kidney (HEK) 293 cells disrupts cholesterol synthesis. PGRMC1 and Cyp51A1 are both highly expressed in the liver-an essential organ in cholesterol metabolism. Based on these findings, I hypothesize that PGRMC1 is a critical regulator of hepatic cholesterol synthesis and is necessary for maintaining systemic cholesterol homeostasis. My aims are to: (1) Determine the function of PGRMC1 in hepatic cholesterol synthesis and (2) Investigate the role of PGRMC1 in systemic sterol homeostasis. Together, these investigations will help elucidate the function of PGRMC1 in cholesterol homeostasis. PUBLIC HEALTH RELEVANCE: Adults with high serum cholesterol levels have an increased risk of cardiovascular disease. This project will determine the function of the novel cytochrome P450 regulator PGRMC1 in hepatic and systemic cholesterol homeostasis. A clear understanding of PGRMC1 function will increase our knowledge of how cholesterol homeostasis is achieved and may reveal new therapeutic approaches for lowering serum cholesterol levels and reducing the prevalence of cardiovascular disease.

描述(由申请人提供)：胆固醇对细胞膜的适当结构和流动性以及膜蛋白的功能是必不可少的。胆固醇也是类固醇、氧化类固醇和胆汁酸的前体。这些代谢物在信号转导中发挥重要作用，对于胆汁酸来说，它还具有脂类增溶作用。血清胆固醇水平升高与心血管疾病(CVD)风险增加相关。对细胞如何调节胆固醇合成的清楚了解将加速开发新的心血管疾病预防和治疗方法。在人类体内，胆固醇的供应由几个因素控制，包括饮食摄入、合成、储存和排泄。胆固醇合成和代谢的关键调节因子是细胞色素P450单加氧酶。从羊毛甾醇合成胆固醇需要P450酶，Cyp51A1。我们实验室最近发现血红素结合蛋白PGRMC1是Cyp51A1的结合伙伴和正调控因子，并证明在人胚胎肾脏(HEK)293细胞中PGRMC1的shRNA敲除会扰乱胆固醇的合成。PGRMC1和Cyp51A1在肝脏中都有高表达，肝脏是胆固醇代谢的重要器官。基于这些发现，我推测PGRMC1是肝脏胆固醇合成的关键调节因子，是维持全身胆固醇稳态所必需的。我的目的是：(1)确定PGRMC1在肝脏胆固醇合成中的作用；(2)研究PGRMC1在全身类固醇平衡中的作用。总之，这些研究将有助于阐明PGRMC1在胆固醇动态平衡中的作用。 公共卫生相关性：血清胆固醇水平高的成年人患心血管疾病的风险增加。该项目将确定新型细胞色素P450调节剂PGRMC1在肝脏和全身胆固醇动态平衡中的功能。对PGRMC1功能的清楚了解将增加我们对胆固醇稳态是如何实现的了解，并可能揭示降低血清胆固醇水平和降低心血管疾病患病率的新的治疗方法。