Endocrine disruptor mediated activation of PXR causes dyslipidemia

内分泌干​​扰物介导的 PXR 激活导致血脂异常

• 批准号: 9308696
• 负责人: Changcheng Zhou
• 金额: $ 33.86万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-26 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9308696
• 关键词: Acute; Adverse effects; Affect; Agonist; Animal Model; Animals; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; CD36 Antigens; Cardiovascular Diseases; Cause of Death; Cells; Chemical Exposure; Chemicals; Chlorinated Hydrocarbons; Cholesterol; Chronic; Citrates; Cosmetics; Development; Diabetes Mellitus; Diet; Disease; Dose; Dyslipidemias; Endocrine Disruptors; Environment; Environmental Risk Factor; Etiology; Exposure to; FDA approved; Food Packaging; Future; Gene Expression; Genetic; Genetic Transcription; Genetic Variation; Goals; Health; Homeostasis; Human; Hyperlipidemia; In Vitro; Individual; Intestines; Knowledge; LDL-Receptor Related Protein 1; Link; Lipids; Liver; Mediating; Medical Device; Modeling; Molecular; Morbidity - disease rate; Mus; Nuclear Receptors; Obesity; Organophosphates; Pesticides; Pharmaceutical Preparations; Pharmacologic Substance; Pilot Projects; Plasma; Plasticizers; Play; Polychlorinated Biphenyls; Receptor Activation; Regulation; Research; Risk Assessment; Role; Testing; Wild Type Mouse; Xenobiotic Metabolism; Xenobiotics; absorption; analog; bisphenol A; cardiovascular disorder risk; cholesterol transporters; disorder risk; environmental chemical; experimental study; gene environment interaction; human disease; humanized mouse; in vivo; interest; mortality; mouse model; novel; packaging material; phthalates; pregnane X receptor; public health relevance; receptor function; sensor; tool; uptake

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.

描述（由申请人提供）：该项目的目标是研究一种将内分泌干扰化学物质（EDC）暴露与血脂异常和心血管疾病联系起来的新机制。孕烷 X 受体 (PXR) 是一种可被多种药物、外源物质和膳食化学品激活的核受体。许多 EDC 都会激活 PXR，包括有机氯和有机磷农药、烷基酚、邻苯二甲酸盐、多氯联苯、双酚 A 及其类似物。然而，PXR 在介导 EDC 对人类和动物的病理生理作用中的作用仍然难以捉摸。越来越多的证据表明 EDC 暴露与人类慢性疾病的发展有关，但人们对这些 EDC 对心血管疾病 (CVD)、肥胖和糖尿病病因的贡献知之甚少。我们最近在动物模型中揭示了 PXR 的促动脉粥样硬化作用，并证明长期 PXR 激活会诱导野生型小鼠出现高脂血症，并增加易发生动脉粥样硬化的载脂蛋白 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 EDC 会导致小鼠高脂血症并加速动脉粥样硬化，从而增加暴露个体患 CVD 的风险。我们提出以下具体目标来检验这一假设：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提高小鼠的血浆脂质水平？ 3) EDC 介导的 PXR 激活对于增加 ApoE-/- 小鼠动脉粥样硬化的发展是否必要且充分？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转化性，将为未来的 EDC 风险评估提供强有力的证据。