A Cardiovascular-NASH disease nexus: Common Mechanisms and Treatments?

项目摘要 整体 尽管开发了越来越有效的疗法来降低致动脉粥样硬化脂蛋白的升高水平， 心血管疾病（CVD）并发症预计将在全球范围内上升，部分原因是由于 肥胖和胰岛素抵抗的发病率。一个紧迫的问题是非酒精性脂肪肝的程度 疾病（NAFLD），其是从脂肪肝到非酒精性脂肪性肝炎（NASH）到肝硬化的范围， 增加CVD风险。在NAFLD患者中，死亡的主要原因是CVD，估计占 占总死亡率的31%。NAFLD和心血管疾病的发展受到组合的影响 遗传和环境因素，其中一些是疾病特异性的，另一些影响两种疾病 流程.我们PPG的总体假设是肝脏脂肪和纤维化预测CVD风险， 针对巨噬细胞中的肝X受体（LXR）、肠道中的法尼基X受体（FXR）的干预措施，以及 肝脏和动脉壁中的氧化特异性表位（OSE）将揭示有助于 NASH和CVD之间的临床关联。重要的是，这些干预措施都利用了 代表性的小分子或抗体，有可能被推进临床试验。识别 已知和未知的风险因素促进NASH和CVD的机制将是重要的 重要性，特别是如果针对这些机制中的一个或多个机制将对两者产生有益影响， 疾病为了实现这一目标，我们提出了一个PPG由四个高度相关的项目和三个核心。 由Christopher Glass博士领导的项目1将测试巨噬细胞中LXR的选择性激活 和枯否细胞与桥甾醇模拟物将导致动脉粥样硬化和NASH的减少，而不引起 脂肪变性或高脂血症。由罗纳德埃文斯博士领导的项目2将调查以下假设： 肠道或肝脏中FXR的选择性激活将导致动脉粥样硬化和NASH的减少。项目三， 由Joseph Witztum博士领导，将测试抗体介导的OSE减少将协调 减少动脉粥样硬化和NASH。由Rohit Loomba博士领导的项目4将调查 肝脂肪含量和纤维化与心血管风险的关系，并使 在项目1、2和3中得出的机械结论。表型核心将使项目1、2和3能够 定量评估小鼠模型中动脉粥样硬化和NASH的程度，并使所有项目获得 来自相关样品的靶向脂质组学谱和细胞因子水平。基因组学和生物信息学核心 将支持项目1、2的基于大规模并行测序的测定（如RNA Seq）的应用 和3并为生物信息学和统计分析提供共享资源。行政核心将 支持PPG的总体行政和科学需求。

PROJECT SUMMARY Overall Despite the development of increasingly effective therapies to reduce elevated levels of atherogenic lipoproteins, cardiovascular disease (CVD) complications are projected to rise worldwide due in part to the increasing incidence of obesity and insulin resistance. An emergent question is the extent to which non-alcoholic fatty liver disease (NAFLD), which is a spectrum ranging from fatty liver to non-alcoholic steatohepatitis (NASH) to cirrhosis, contributes to CVD risk. Among patients with NAFLD, the leading cause of death is CVD, estimated to account for 31% of total mortality. The development of NAFLD and cardiovascular disease is influenced by combinations of genetic and environmental factors, some of which are disease-specific and others that affect both disease processes. The overall hypotheses of our PPG are that liver fat and fibrosis predict CVD risk and that interventions targeting Liver X receptors (LXRs) in macrophages, the farnesyl X receptor (FXR) in the gut, and oxidation specific epitopes (OSEs) in the liver and artery wall will reveal common mechanisms that contribute to the clinical association between NASH and CVD. Importantly, each of these interventions make use of representative small molecules or antibodies that have the potential to be advanced for clinical trials. Identifying mechanisms by which known and unknown risk factors promote both NASH and CVD would be of great significance, especially if targeting one or more of these mechanisms would produce beneficial effects on both diseases. To achieve this goal, we propose a PPG consisting of four highly inter-related projects and three cores. Project 1, led by Dr. Christopher Glass, will test the hypothesis that selective activation of LXRs in macrophages and Kupffer cells with desmosterol mimetics will result in reductions of atherosclerosis and NASH without causing steatosis or hypertriglyceridemia. Project 2, led by Dr. Ronald Evans, will investigate the hypothesis that selective activation of FXR in the gut or liver will result in reductions in atherosclerosis and NASH. Project 3, led by Dr. Joseph Witztum, will test the hypothesis that antibody-mediated reductions in OSEs will coordinately reduce both atherosclerosis and NASH. Project 4, led by Dr. Rohit Loomba, will investigate the relationships of liver fat content and fibrosis with cardiovascular risk in human subjects and enable translational extension of mechanistic findings made in Projects 1, 2 and 3. A Phenotyping Core will enable Projects 1, 2 and 3 to quantitatively evaluate extent of atherosclerosis and NASH in mouse models, and enable all projects to obtain targeted lipidomic profiles and cytokine levels from relevant samples. A Genomics and Bioinformatics Core will support the application of massively parallel sequencing-based assays, such as RNA Seq, by Projects 1, 2 and 3 and provide a shared resource for bioinformatics and statistical analysis. An Administrative Core will support the overall administrative and scientific needs of the PPG.