The role of PGRMC1 in hepatic cholesterol homeostasis

PGRMC1 在肝脏胆固醇稳态中的作用

• 批准号: 8210363
• 负责人: Rita Thomas Brookheart
• 金额: $ 5.22万
• 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/8210363
• 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; public health relevance; 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）：胆固醇对于细胞膜的适当结构和流动性以及膜蛋白的功能至关重要。胆固醇也是类固醇，氧蛋白酶和胆汁酸的前体。这些代谢产物在信号转导中起重要功能，而在胆汁酸的情况下，脂质溶解化。血清胆固醇水平升高与心血管疾病（CVD）的风险增加有关。对细胞如何调节胆固醇合成的清晰了解将加速新型预防和治疗方法的CVD。在人类中，体内胆固醇的供应受到饮食摄入，合成，储存和排泄的几个因素的控制。胆固醇合成和代谢的关键调节剂是细胞色素P450单加氧酶。 lanosterol的胆固醇的合成需要P450酶CYP51A1。我们的实验室最近将血红素结合蛋白PGRMC1确定为CYP51A1的结合伴侣和阳性调节剂，并证明了人类胚胎肾脏（HEK）293个细胞中PGRMC1的shRNA敲低破坏了胆固醇的合成。 PGRMC1和CYP51A1在胆固醇代谢中的肝脏基本器官中都高度表达。根据这些发现，我假设PGRMC1是肝胆固醇合成的关键调节剂，对于维持全身胆固醇的稳态是必不可少的。我的目的是：（1）确定PGRMC1在肝胆固醇合成中的功能，（2）研究PGRMC1在全身固醇稳态中的作用。总之，这些研究将有助于阐明PGRMC1在胆固醇稳态中的功能。 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在肝和系统性胆固醇稳态中的功能。对PGRMC1功能的清晰了解将增加我们对如何实现胆固醇稳态的了解，并可能揭示出新的治疗方法来降低血清胆固醇水平并降低心血管疾病的患病率。