Endocrine disruptor mediated activation of PXR causes dyslipidemia and atherosclerosis

项目摘要 尽管在诊断技术和有效治疗方面取得了重大进展， 心血管疾病（CVD）仍然是全世界死亡率和发病率的主要原因。最近大- 大规模的人体研究表明，暴露于内分泌干扰物（EDCs）之间存在一种新的联系， 和CVD。然而，暴露于EDCs如何影响CVD风险仍然知之甚少，并继续 妨碍合理评估EDC暴露的健康风险。我们以前发现过很多塑料- 相关的内分泌干扰物作为外源性生物素传感器PXR的有效激动剂，它提供了 这是研究EDC暴露影响疾病的新机制的重要工具。我们 该实验室首次揭示了PXR在动脉粥样硬化发展中的调节作用， 并且还证明了几种广泛使用的EDCs通过以下途径增加动脉粥样硬化和血脂异常 小鼠模型中的PXR信号传导。了解EDC诱导的细胞凋亡的详细机制， 血脂异常和动脉粥样硬化，已经产生了新的组织特异性PXR敲除小鼠， 初步研究表明，暴露于一种新发现的PXR激动剂EDC， 脂质吸收、高脂血症和PXR依赖性肝脂肪变性。此外，EDC介导的 PXR激活导致神经酰胺循环水平升高，神经酰胺是一类生物活性鞘脂， 与人类CVD风险增加独立相关。我们令人兴奋的初步发现支持了 中心假设，塑料相关的内分泌干扰物，激活PXR刺激肠道脂质吸收， 神经酰胺产生，导致血脂异常增加、肝脂肪变性和动脉粥样硬化。我们提出 三个具体的目标来检验这一假设：1）确定PXR信号传导的组织特异性贡献 使用新的条件性基因敲除小鼠对EDC诱导的血脂异常和神经酰胺产生的影响; 2）定义 PXR激动性EDCs通过其调节脂质和神经酰胺稳态的肝肠信号传导;和 3)确定EDC介导的PXR激活对动脉粥样硬化发展的影响。影响的 化学环境对人类健康的影响已成为人们强烈关注的主题，但很少有研究 EDC的研究领域主要集中在EDC对动脉粥样硬化发展的影响。此续订 应用将扩大我们最初的研究范围，追求新的研究方向，利用新开发的 动物模型，并结合联合收割机在体外、离体和体内的方法来研究EDC的致动脉粥样硬化作用。 拟议的研究将有助于我们理解“基因-EDC相互作用”在易感性 个体动脉粥样硬化和其他慢性疾病。

PROJECT SUMMARY Despite major advances in developing diagnostic techniques and effective treatments, atherosclerotic cardiovascular disease (CVD) is still the leading cause of mortality and morbidity worldwide. Recent large- scale human studies have implicated a novel link between exposure to endocrine disrupting chemicals (EDCs) and CVD. However, how exposure to EDCs influences CVD risk is still poorly understood, and continues to hamper rational assessment of the health risks of EDC exposure. We have previously identified many plastic- associated EDCs as potent agonists of the xenobiotic sensor pregnane X receptor (PXR), which has provided an important tool for the study of new mechanisms through which EDC exposure impacts diseases. Our laboratory was the first to reveal the novel function of PXR in the regulation of atherosclerosis development, and has also demonstrated that several widely-used EDCs increase atherosclerosis and dyslipidemia through PXR signaling in mouse models. To understand the detailed mechanisms underlying EDC-induced dyslipidemia and atherosclerosis, novel tissue-specific PXR knockout mice have been generated, and preliminary studies demonstrated that exposure to a newly identified PXR agonistic EDC increased intestinal lipid absorption, hyperlipidemia, and hepatic steatosis in a PXR-dependent manner. Further, EDC-mediated PXR activation led to elevated circulating levels of ceramides, a class of bioactive sphingolipids that has been independently associated with increased CVD risk in humans. Our exciting preliminary findings support a central hypothesis that plastic-associated EDCs that activate PXR stimulate intestinal lipid absorption and ceramide production, leading to increased dyslipidemia, hepatic steatosis, and atherosclerosis. We propose three specific aims to test this hypothesis: 1) Determine the tissue-specific contribution of PXR signaling towards EDC-induced dyslipidemia and ceramide production using novel conditional knockout mice; 2) Define the enterohepatic signaling through which PXR agonistic EDCs regulate lipid and ceramide homeostasis; and 3) Determine the impact of EDC-mediated PXR activation on atherosclerosis development. Influences of the chemical environment on human health have become the subject of intense interest but very few studies in the EDC research field have focused on the impact of EDCs on atherosclerosis development. This renewal application will expand our initial research scope, pursue new research directions, utilize newly developed animal models, and combine in vitro, ex vivo, and in vivo approaches to investigate EDCs’ atherogenic effects. The proposed studies will contribute to our understanding of “gene-EDC interactions” in predisposing individuals to atherosclerosis and other chronic diseases.