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

项目总结 总括 尽管开发了越来越有效的治疗方法来降低升高的致动脉粥样硬化性脂蛋白水平， 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 肥胖和胰岛素抵抗的发生率。一个紧迫的问题是，非酒精性脂肪肝在多大程度上 疾病(NAFLD)，从脂肪肝到非酒精性脂肪性肝炎(NASH)再到肝硬变， 会增加心血管疾病的风险。在非酒精性脂肪肝患者中，主要死亡原因是心血管疾病，据估计 占总死亡率的31%。NAFLD和心血管疾病的发展受多种因素的影响 遗传和环境因素，其中一些是疾病特有的，另一些影响这两种疾病 流程。我们PPG的总体假设是肝脏脂肪和纤维化可以预测心血管疾病的风险，而且 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，以及 肝脏和动脉壁中的氧化特异性表位(OS)将揭示有助于 NASH与CVD的临床相关性。重要的是，这些干预中的每一个都利用了 具有代表性的小分子或抗体，有可能被推进到临床试验。识别 已知和未知风险因素促进NASH和CVD的机制将是非常重要的 意义重大，特别是如果针对这些机制中的一个或多个会对两者都产生有利影响 疾病。为了实现这一目标，我们提出了一个由四个高度相关的项目和三个核心组成的PPG。 项目1由克里斯托弗·格拉斯博士领导，将测试巨噬细胞中LXRs选择性激活的假设 而Kupffer细胞和类似于Desmosterol的细胞将导致动脉粥样硬化和NASH的减少，而不会导致 脂肪变性或高甘油三酯血症。由罗纳德·埃文斯博士领导的项目2将调查以下假设 选择性激活肠道或肝脏中的FXR将导致动脉粥样硬化和NASH的减少。项目3， 由约瑟夫·维茨塔姆博士领导，将检验抗体介导的OS减少将协调的假设 减少动脉粥样硬化和NASH。项目4，由罗希特·伦巴博士领导，将调查 肝脂肪含量和肝纤维化与心血管风险的关系，并使翻译扩展成为可能 项目1、2和3中的机械性发现。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，并使所有项目能够获得 相关样本的靶向脂肪组谱和细胞因子水平。基因组学和生物信息学的核心 将通过项目1、2支持大规模并行测序分析的应用，如RNA Seq 和3，为生物信息学和统计分析提供共享资源。行政核心意志 支持PPG的总体管理和科学需求。

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.