Endocrine disruptor mediated activation of PXR causes dyslipidemia

描述（由申请人提供）：本项目的目标是研究将内分泌干扰物（EDCs）暴露与血脂异常和心血管疾病联系起来的新机制。PXR是一种由多种药物、外源性化学物质和膳食化学物质激活的核受体。许多内分泌干扰物激活PXR，包括有机氯和有机磷农药，烷基酚，邻苯二甲酸酯，多氯联苯，双酚A及其类似物。然而，PXR在人类和动物中介导内分泌干扰物的病理生理学作用的作用仍然是难以捉摸的。越来越多的证据表明EDC暴露与人类慢性疾病的发展有关，但这些EDC对心血管疾病（CVD）、肥胖和糖尿病的病因学的贡献却知之甚少。我们最近在动物模型中揭示了PXR的促动脉粥样硬化作用，并证明了慢性PXR激活诱导野生型小鼠高脂血症，并增加动脉粥样硬化倾向载脂蛋白E缺陷（ApoE-/-）小鼠的动脉粥样硬化。我们的中心假设是，激活PXR的EDCs会导致小鼠高脂血症和加速动脉粥样硬化，从而增加暴露个体的CVD风险。我们提出以下具体目标来验证这一假设：1）肠道PXR激活诱导高脂血症的分子机制是什么？2)暴露于FDA批准的邻苯二甲酸酯替代增塑剂如何升高小鼠的血脂水平？3)EDC介导的PXR激活是否是增加ApoE-/-小鼠动脉粥样硬化发展的必要和充分条件？我们的研究将确定PXR在将暴露于EDC与高脂血症和CVD联系起来中的作用，并将提供解释EDC暴露如何导致动脉粥样硬化效应的新机制联系。这些研究具有广泛的转化性，将为未来的内分泌干扰物风险评估提供强有力的证据。

DESCRIPTION (provided by applicant): The goal of this project is to investigate a novel mechanism linking exposure to endocrine disrupting chemicals (EDCs) with dyslipidemia and cardiovascular disease. The pregnane X receptor (PXR) is a nuclear receptor activated by numerous drugs, xenobiotic and dietary chemicals. Many EDCs activate PXR, including organochlorine and organophosphate pesticides, alkylphenols, phthalates, polychlorinated biphenyls, bisphenol A and its analogs. However, the role of PXR in mediating the pathophysiological effects of EDCs in humans and animals remains elusive. Mounting evidence implicates EDC exposure in the development of chronic human diseases but the contribution of these EDCs to the etiology of cardiovascular disease (CVD), obesity, and diabetes is poorly understood. We have recently revealed the pro-atherogenic effects of PXR in animal models and demonstrated that chronic PXR activation induces hyperlipidemia in wild-type mice and increases atherosclerosis in atherosclerosis-prone apolipoprotein E deficient (ApoE-/-) mice. Our central hypothesis is that EDCs which activate PXR will lead to hyperlipidemia and accelerated atherosclerosis in mice, thereby increasing the risk of CVD in exposed individuals. We propose the following specific aims to test this hypothesis: 1) What are the molecular mechanisms through which intestinal PXR activation induces hyperlipidemia? 2) How does exposure to FDA-approved phthalate substitute plasticizers elevate plasma lipid levels in mice? 3) Is EDC-mediated PXR activation necessary and sufficient to increase atherosclerosis development in ApoE-/- mice? Our research will establish the role of PXR in linking exposure to EDCs with hyperlipidemia and CVD, and will provide novel mechanistic links explaining how EDC exposure causes atherogenic effects. These studies are broadly translational and will provide strong evidence to inform future risk assessment for EDCs.