Endocrine disruptor mediated activation of PXR causes dyslipidemia and atherosclerosis

项目总结 尽管在开发诊断技术和有效治疗方面取得了重大进展，但动脉粥样硬化 心血管疾病(CVD)仍然是世界范围内死亡和发病的主要原因。最近的大型- 大规模的人体研究表明，暴露于内分泌干扰物(EDCs)之间存在新的联系 和心血管疾病。然而，暴露于内皮细胞对心血管疾病风险的影响仍然知之甚少，并将继续下去。 妨碍对EDC暴露的健康风险进行理性评估。我们之前已经发现了许多塑料- 相关的EDCs作为异种传感器孕烷X受体(PXR)的有效激动剂，它已经提供了 这是研究EDC暴露影响疾病的新机制的重要工具。我们的 实验室第一个揭示了PXR在调节动脉粥样硬化发展中的新功能， 也证明了几种广泛使用的内皮细胞通过增加动脉粥样硬化和血脂紊乱 小鼠模型中的PXR信号转导。了解EDC诱导的详细机制 血脂异常和动脉粥样硬化，已经产生了新的组织特异性PXR基因敲除小鼠，并且 初步研究表明，接触一种新发现的PXR激动剂EDC会增加肠道 PXR依赖的方式导致脂质吸收、高脂血症和肝脏脂肪变性。此外，由EDC调解 PXR激活导致循环中神经酰胺水平升高，神经酰胺是一类具有生物活性的鞘磷脂，已被 与人类心血管疾病风险增加独立相关。我们令人兴奋的初步发现支持 中心假设，激活PXR的塑料相关内皮细胞刺激肠道脂肪吸收和 神经酰胺的产生，导致血脂紊乱、肝脏脂肪变性和动脉粥样硬化。我们建议 验证这一假说的三个具体目标：1)确定PXR信号的组织特异性贡献 利用新的条件性基因敲除小鼠研究EDC诱导的血脂异常和神经酰胺的产生；2)定义 PXR激动型内皮细胞调节脂质和神经酰胺动态平衡的肠-肝信号转导； 3)确定EDC介导的PXR激活对动脉粥样硬化发展的影响。对中国经济的影响 化学环境对人体健康的影响已成为人们非常感兴趣的课题，但在这方面的研究却很少。 EDC的研究领域主要集中在EDC在动脉粥样硬化发展中的作用。此次续订 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，并结合体外、体外和体内的方法来研究内皮细胞的致动脉粥样硬化作用。 建议的研究将有助于我们理解易感中的“基因-eDC相互作用”。 个人易患动脉粥样硬化等慢性病。

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.