Identification of Novel Genes/Pathways That Regulate Atherogenesis

项目摘要 项目摘要：高胆固醇血症是动脉粥样硬化的独立危险因素，最常见 冠状动脉疾病(CAD)的病因。大量的临床前和临床研究表明， 降低血浆低密度脂蛋白(LDL-C)水平和/或增强高密度脂蛋白功能是有效的方法 以降低冠心病的发生率。肝脏在维持胆汁酸(BA)、甘油三酯(TG)和 通过协调一些基因和信号通路的调节来实现胆固醇的动态平衡。正在激活 转录因子3(ATF3)是鸡传染性支气管炎病毒ATF/cAMP反应元件结合(ATF/CREB)家族的成员。 转录因子，并被证明能抑制巨噬细胞的炎症反应。到目前为止，肝脏的作用 ATF3在调节胆固醇或胆汁酸代谢中的作用完全不清楚。我们的初步研究已经 表明肝脏ATF3可能通过协调血浆胆固醇摄取来调节血浆胆固醇水平 受肝脏和BA代谢的影响。因此，肝脏ATF3可能调节血管紧张素转换酶的发生或消退。 动脉硬化。在这个项目中，我们将同时使用增益法和损失法来检验这一假设。 我们的研究可能有助于确定肝脏ATF3是一种新的胆固醇和胆汁酸代谢调节剂，并 动脉硬化。

Project Summary Project Summary: Hypercholesterolemia is an independent risk factor for atherosclerosis, the most common cause for coronary artery disease (CAD). Numerous preclinical and clinical studies have demonstrated that lowering plasma LDL cholesterol (LDL-C) levels and/or enhancing HDL functionality are effective approaches to lower the incidence of CAD. The liver plays a central role in maintaining bile acid (BA), triglyceride (TG) and cholesterol homeostasis by coordinating regulation of a number of genes and signaling pathways. Activating transcription factor 3 (ATF3) is a member of the ATF/cAMP response element-binding (ATF/CREB) family of transcription factors, and is shown to inhibit inflammatory response in macrophages. So far, the role of hepatic ATF3 in regulating cholesterol or bile acid metabolism is completely unknown. Our preliminary studies have shown that hepatic ATF3 regulates plasma cholesterol levels likely by coordinating plasma cholesterol uptake by the liver and BA metabolism. As a result, hepatic ATF3 may regulate the development or regression of atherosclerosis. In this project, we will use both gain- and loss-of-function approaches to test this hypothesis. Our studies may help identify hepatic ATF3 as a novel regulator of cholesterol and bile acid metabolism and atherosclerosis.