Endocrine disruptor mediated activation of PXR causes dyslipidemia

描述(由申请人提供)：本项目的目标是调查一种新的机制，将暴露于内分泌干扰物(EDCs)与血脂异常和心血管疾病联系起来。孕烷X受体(PXR)是一种核受体，可被多种药物、异物和饮食化学物质激活。许多内分泌细胞激活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在介导内皮样细胞在人类和动物中的病理生理效应中的作用仍然不清楚。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在心血管疾病(CVD)、肥胖和糖尿病的病因中的作用尚不清楚。我们最近在动物模型中揭示了PXR的促动脉粥样硬化作用，并证明慢性PXR激活会导致野生型小鼠的高脂血症，并增加动脉粥样硬化易患载脂蛋白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动脉粥样硬化加速，从而增加接触者患心血管疾病的风险。我们提出以下具体目标来验证这一假说：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类塑化剂如何提高小鼠的血脂水平？3)EDC介导的PXR激活对于促进ApoE-/-小鼠动脉粥样硬化的发展是必要的且充分的吗？我们的研究将确定PXR在EDC暴露与高脂血症和CVD之间的联系中的作用，并将提供新的机制联系来解释EDC暴露如何导致动脉粥样硬化效应。这些研究具有广泛的翻译性，将为发展中国家未来的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.