PFAS accelerate atherosclerosis through modulation of bile acid metabolism

PFAS 通过调节胆汁酸代谢加速动脉粥样硬化

基本信息

批准号：
10658104
负责人：
Michael Curtis Petriello
金额：
$ 164.42万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-19 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10658104
关键词：
ASBT protein Acceleration Aorta Arterial Fatty Streak Atherogenic Diet Atherosclerosis Bile Acids Blood Cardiometabolic Disease Cardiovascular Diseases Cause of Death Chemicals Cholesterol Clinical Community Health Coronary heart disease Correlation Studies Data Dietary Cholesterol Enterohepatic Circulation Environment Excretory function Experimental Models Exposure to Female Genes Goals Health Surveys High Density Lipoproteins Human Image Label Lead Length Lesion Link Lipids Low Density Lipoprotein Receptor Low-Density Lipoproteins Measures Mediating Mediation Methods Modeling Monitor Mus Myocardial Infarction Oils Outcome Output Pathologic Pathway interactions Pattern Pharmacologic Substance Phytosterols Poly-fluoroalkyl substances Property Publishing Reporting Risk Factors Rodent Rodent Model Role Sampling Serum Sterols Stroke Testing Time Toxic effect Toxicity Tests Toxicokinetics United States Very low density lipoprotein Wild Type Mouse absorption arm atherosclerosis risk bile acid metabolism cardiometabolic risk cardiovascular disorder risk cholesterol absorption cohort consumer product design dietary epidemiology study ileum lipoprotein cholesterol male man perfluorooctane sulfonate pollutant preclinical study reuptake surfactant

项目摘要

PROJECT SUMMARY Cardiovascular diseases are the leading cause of death in the United States and worldwide, and atherosclerotic heart disease is particular burdensome. Per- and polyfluoroalkyl substances (PFAS) are a class of ubiquitous man-made chemicals that have been associated with increased risk factors for cardiometabolic disease (i.e., increased circulating cholesterol), or major outcomes related to atherosclerosis including stroke/heart attacks in epidemiological studies. No studies have reported on PFAS accelerated atherosclerosis using rodent models. Recent rodent studies have shown PFAS can increase circulating cholesterol, but these studies have relied primarily on wildtype mice which display lipoprotein cholesterol fraction patterns (VLDL, LDL, HDL) that are opposite of humans, and which do not develop lesions within the aorta. To circumvent this problem and to have an experimental model from which results can be directly extrapolated to humans, we will use Low Density Lipoprotein Receptor deficient mice (Ldlr -/-), which have lipid profiles like humans, to determine if PFAS- mediated increases in cholesterol levels lead to pathological atherosclerosis. Recently, we published that wildtype mice fed an atherogenic diet and exposed to a simple mixture of 5 environmentally relevant PFAS (PFOS, PFOA, PFNA, PFHxS, and GenX) for 12 weeks resulted in increased circulating cholesterol and bile acids. In preliminary studies, we followed the same exposure paradigm and observed increased circulating cholesterol in Ldlr -/- mice. Here, we propose to extend our initial observations using a simple PFAS mixture to a full factorial design and examine atherosclerotic lesion formation. Circulating cholesterol levels can be modulated through mechanisms related to dietary cholesterol absorption, de-novo cholesterol synthesis, and fecal excretion. Our preliminary studies show that Ldlr -/- mice exposed to the mixture show decreased bile acid excretion and induction of reuptake transporters in the ileum (especially apical sodium dependent bile acid transporter; ASBT). Our proposed studies will use pharmaceuticals selective for ASBT and mass labeled sterols to confirm ASBT induction is critical. Finally, to validate some of these observations in a human cohort, we recently measured PFAS in serum from the Anniston Community Health Surveys (ACHS) and we reported that residents were highly exposed to PFOS, and we now propose to measure bile acids in stored samples. We will use mixture methods to show 1) PFAS mixtures statistically correlate with increased cholesterol, and 2) these associations are mediated through increases in circulating bile acids. We hypothesize that PFAS accelerate atherosclerosis by altering cholesterol excretion as bile acids. Our specific aims are: 1) To test the hypothesis that mixtures of environmentally relevant PFAS accelerate atherosclerosis in Ldlr -/- mice. 2) To test the hypothesis that PFAS disrupts bile acid reuptake leading to increases in circulating cholesterol through ASBT- related mechanisms. 3) To examine the association between PFAS mixtures and circulating bile acids and test if that the association between PFAS mixtures and cholesterol can be explained by increases in these.

项目摘要心血管疾病是美国和全球的主要死亡原因，动脉粥样硬化心脏病特别繁重。每种和多氟烷基物质（PFA）是一类无处不在的与心脏代谢疾病风险因素增加有关的人为化学物质（即增加循环胆固醇）或与动脉粥样硬化有关的主要结果，包括中风/心脏病发作流行病学研究。尚无有关使用啮齿动物模型加速PFA的研究。最近的啮齿动物研究表明，PFA可以增加循环胆固醇，但这些研究依赖于主要是关于显示脂蛋白胆固醇分数图案（VLDL，LDL，HDL）的野生型小鼠与人类相反，并且不会在主动脉内部发展病变。解决这个问题并有一个实验模型，可以将结果直接推送到人类，我们将使用低密度脂蛋白受体缺乏小鼠（LDLR - / - ）具有像人类一样的脂质特征，以确定PFAS-是否是否PFAS- 介导的胆固醇水平增加导致病理动脉粥样硬化。最近，我们发表了野生型小鼠喂养动脉粥样硬化饮食，并暴露于5种与环境相关的PFA的简单混合物（PFO，PFOA，PFNA，PFHXS和GENX）持续12周，导致循环胆固醇和胆汁增加酸。在初步研究中，我们遵循相同的暴露范式并观察到循环增加 LDLR - / - 小鼠中的胆固醇。在这里，我们建议使用简单的PFA混合物扩展我们的初始观察结果完整的阶乘设计并检查动脉粥样硬化病变的形成。循环胆固醇水平可能是通过与饮食中胆固醇吸收，De-Novo胆固醇合成和粪便排泄。我们的初步研究表明，暴露于混合物的LDLR - / - 小鼠显示胆汁酸会降低回肠中再摄取转运蛋白的排泄和诱导（尤其是依赖钠的胆汁酸转运蛋白； ASBT）。我们提出的研究将使用药物选择性用于ASBT和质量标记的固醇确认ASBT诱导至关重要。最后，为了验证人类队列中的某些观察结果，我们最近测量了Anniston社区健康调查（ACHS）血清中的PFA，我们报告说居民高度暴露于PFO，我们现在建议测量存储样品中的胆汁酸。我们将使用混合方法显示1）PFAS混合物在统计上与胆固醇统计相关，而2）通过增加循环胆汁酸来介导关联。我们假设PFA会加速动脉粥样硬化通过改变胆固醇的排泄作为胆汁酸。我们的具体目的是：1）检验假设与环境相关的PFA的混合物在LDLR - / - 小鼠中加速了动脉粥样硬化。 2）测试假设PFA会破坏胆汁酸再摄取，从而导致通过ASBT-循环胆固醇增加相关机制。 3）检查PFA混合物与循环胆汁酸之间的关联并测试如果PFA混合物与胆固醇之间的关联可以通过增加的增加来解释。