Post-Translational Regulation of Lipid Metabolism

摘要 血浆胆固醇、甘油三酯升高和肥胖等代谢并发症都在其中 心血管疾病(CVD)最重要的危险因素。了解影响因素和 调节血浆低密度脂蛋白胆固醇水平的机制是最重要的 重要性。肝脏低密度脂蛋白受体(LDLR)表达增加导致低密度脂蛋白摄取增加 胆固醇从循环中释放，并已成为治疗心血管疾病和 血脂异常。在这里，我们发现了一个调节肝脏低密度脂蛋白受体和血浆低密度脂蛋白胆固醇的新基因。 在人类全基因组关联研究中，这也是低密度脂蛋白水平的一个位置。在广泛的 初步数据显示，过度表达和沉默(使用反义寡核苷酸， 体内候选基因的ASOS)也改变了血浆总胆固醇和低密度脂蛋白的水平，以及 相互调节LDLR，表明其作用机制是通过直接针对 LDLR。在具体目标1中，我们将确定分子机制和结构要求 低密度脂蛋白受体蛋白表达和血浆低密度脂蛋白水平的调节。在具体目标2中，我们 将使用免费的体内功能获得和丧失模型，包括组织特异性基因敲除 小鼠和ASO，以确定特定的ASO沉默药物在相关的治疗潜力 动脉粥样硬化的疾病模型。在目前的提案中，我们描述了一种新的后翻译 调节血浆胆固醇稳态的途径。我们的发现发现了一个新的帖子- 可被ASO沉默试剂靶向的翻译调控，因此具有重要意义 治疗潜力。

ABSTRACT Elevated plasma cholesterol, triglycerides and metabolic complications such as obesity are among the most important risk factors for cardiovascular disease (CVD). Understanding the factors and mechanisms that regulate plasma low-density lipoprotein (LDL) cholesterol levels is of the utmost importance. Increasing hepatic LDL receptor (LDLR) expression leads to increased uptake of LDL cholesterol from the circulation, and has been a successful therapeutic strategy for treating CVD and dyslipidemia. Here, we identify a novel gene that regulates hepatic LDLR and plasma LDL cholesterol levels that is also a locus for LDL-C levels in human Genome-wide Association Studies. In extensive preliminary data, we show that overexpression and silencing (using antisense oligonucleotides, ASOs) of the candidate gene in vivo also alters plasma total and LDL cholesterol levels, and reciprocally regulates the LDLR, suggesting the mechanism of action is directly through targeting the LDLR. In Specific Aim 1 we will determine the molecular mechanism and structural requirements of the regulation of LDLR protein expression and plasma LDL cholesterol levels. In Specific Aim 2, we will use complimentary in vivo gain- and loss-of-function models, including tissue-specific knockout mice and ASOs, to determine the therapeutic potential of specific ASO silencing agents in a relevant disease model of atherosclerosis. In the current proposal we describe a novel post-translational pathway that modulates plasma cholesterol homeostasis. Our findings identify a novel post- translational regulation that can be targeted with ASO silencing agents and therefore has significant therapeutic potential.