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

基本信息

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
项目类别：
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

项目摘要

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）：该项目的目的是研究一种与血脂异常和心血管疾病的内分泌破坏化学物质（EDC）联系起来的新型机制。妊娠X受体（PXR）是一种核受体，该核受体被许多药物，异种和饮食化学物质激活。许多EDC激活PXR，包括有机氯和有机磷酸盐农药，烷基苯酚，邻苯二甲酸盐，多氯联苯，双苯基A及其类似物。但是，PXR在介导EDC在人类和动物中的病理生理影响中的作用仍然难以捉摸。越来越多的证据表明，EDC在慢性人类疾病的发展中暴露，但这些EDC对心血管疾病（CVD），肥胖和糖尿病的病因的贡献知之甚少。我们最近揭示了PXR在动物模型中的促动脉粥样硬化作用，并证明慢性PXR激活诱导野生型小鼠中的高脂血症，并增加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将导致高脂血症并加速小鼠的动脉粥样硬化，从而增加暴露的个体CVD的风险。我们提出以下特定目的来检验这一假设：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化增塑剂如何提高小鼠的血浆脂质水平？ 3）EDC介导的PXR激活是否需要且足以增加APOE - / - 小鼠的动脉粥样硬化发展？我们的研究将确定PXR在将EDC与高脂血症和CVD连接起来的作用，并将提供新的机械联系，以解释EDC暴露如何引起动脉粥样硬化作用。这些研究是广泛的转化，将提供有力的证据，以告知EDC的未来风险评估。