The role of PGRMC1 in hepatic cholesterol homeostasis

描述（由申请人提供）：胆固醇对细胞膜的正常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、氧化甾醇和胆汁酸的前体。这些代谢物在信号转导中起重要作用，在胆汁酸的情况下，起脂质溶解作用。血清胆固醇水平升高与心血管疾病（CVD）风险增加有关。清楚地了解细胞如何调节胆固醇合成将加速心血管疾病预防和治疗新方法的发展。在人体内，胆固醇的供应受几个因素控制，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。我们的实验室最近发现血红素结合蛋白PGRMC1是Cyp51A1的结合伙伴和正调节因子，并证明在人胚胎肾（HEK） 293细胞中shRNA敲低PGRMC1会破坏胆固醇合成。PGRMC1和Cyp51A1均在肝脏中高表达，肝脏是胆固醇代谢的重要器官。基于这些发现，我假设PGRMC1是肝脏胆固醇合成的关键调节因子，对于维持全身胆固醇稳态是必要的。我的目标是：(1)确定PGRMC1在肝脏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。

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.