Soluble epoxide hydrolase: assessment of in vivo activity and regulation by gut microbiota

可溶性环氧化物水解酶：体内活性评估和肠道微生物群的调节

基本信息

批准号：
10580709
负责人：
JANG H. YOUN
金额：
$ 40.85万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-24 至 2025-02-25
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10580709
关键词：
Acids Animals Antibiotic Therapy Antibiotics Arachidonic Acids Bile Acids Blood Blood Pressure Cardiovascular Abnormalities Cardiovascular Diseases Cardiovascular system Data Deoxycholic Acid Detection Development Diabetes Mellitus Endothelium Enzymes Epoxide hydrolase Epoxy Compounds Fatty acid glycerol esters Genetic Polymorphism Glycols Health Hepatic Human Hydrolase In Vitro Individual Insulin Resistance Lithocholic Acid Liver Measurable Measures Mediating Metabolic Metabolic Diseases Metabolism Methods Pathologic Performance Physiological Plasma Production Rattus Regulation Research Personnel Role Sample Size Secondary to Testing Time Time Study Tissues blood glucose regulation cardiovascular health cost diabetic dietary endothelial dysfunction feeding gut bacteria gut microbiota human disease improved in vivo indexing inhibitor lipid mediator metabolomics new therapeutic target novel tool treatment effect

项目摘要

Epoxyeicosatrienoic acids (EETs) are lipid mediators with beneficial effects on metabolic and cardiovascular (CV) health. EETs and other FFA epoxides are quickly metabolized to biologically less active diols by soluble epoxide hydrolase (sEH). Inhibition of sEH, which increases EETs, improves metabolic and CV health and is proposed as an effective strategy to treat diabetes and CV diseases. Despite its importance to health, how sEH is regulated in vivo is poorly understood, particularly in humans where sEH is difficult to study, largely due to limited access to individual tissues where sEH is expressed or lack of appropriate tools to assess sEH activity. sEH activity is often inferred in human studies by measuring FFA epoxide-diol ratios in the blood. As many as 15 FFA epoxide-diol pairs can be measured in blood. We recently developed a new method to estimate sEH activity in vivo, which combines metabolomic determination and simultaneous analysis of all measurable epoxide-diol pairs. This method⎯Simultaneous Analysis of Multiple Indices (SAMI)⎯markedly increases the power to detect changes (or group differences) in sEH activity. This is important, especially in human studies, as increased power allows detection of treatment effects with smaller sample sizes, reducing cost. One objective of this proposal is to evaluate the performance of our new metabolomic approach, SAMI, in detecting changes in sEH activity or EET metabolism under various conditions in animals, before it can be widely applied to human studies. Using SAMI, our recent study showed that sEH activity decreased profoundly after a meal in rats. Interestingly, this effect was completely abolished in animals with gut bacteria depleted by antibiotic treatment, suggesting that gut bacteria may be involved in the postprandial effect. Our preliminary data suggest the intriguing possibility that lithocholic acid (LCA), a secondary bile acid produced by gut bacteria, may be an endogenous inhibitor of sEH, mediating the postprandial regulation of sEH activity. Another objective of this proposal is to validate this novel mechanism of postprandial sEH regulation involving LCA. Thus, the proposed studies will explore a novel mechanism for sEH regulation in vivo and evaluate the performance of our new method to assess sEH activity based on plasma oxylipins. Successful completion of the proposed studies would facilitate studies of sEH regulation in vivo in animals and humans and lead to new therapeutic targets or strategies in the treatment of diabetes or CV diseases.

环氧二十碳三烯酸 (EET) 是对代谢和心血管 (CV) 健康有益的脂质介质，EET 和其他 FFA 环氧化物可通过可溶性环氧化物水解酶 (sEH) 快速代谢为生物活性较低的二醇，从而增加 EET，从而改善。尽管 sEH 对健康很重要，但它被认为是治疗糖尿病和心血管疾病的有效策略。人们对体内调节的了解甚少，特别是在人类中，sEH 很难研究，这主要是由于对表达 sEH 的个体组织的访问有限，或者在人类研究中经常通过测量 FFA 来推断 sEH 活性评估缺乏适当的工具。我们最近开发了一种估计血液中 sEH 活性的新方法，该方法结合了血液中多达 15 个 FFA 环氧二醇对。对所有可测量的环氧化物-二醇对进行代谢组学测定和同步分析，这种方法——多重指数同步分析 (SAMI)——显着提高了检测 sEH 活性变化（或群体差异）的能力，这很重要，尤其是在人类研究中。由于功率增加可以用较小的样本量检测治疗效果，因此该提案的一个目标是评估我们的新代谢组学方法 SAMI 在检测变化方面的性能。在广泛应用于人类研究之前，我们最近的研究表明，在动物体内各种条件下的 sEH 活性或 EET 代谢显着降低，这表明这种效应在有肠道的动物中完全消失。细菌被抗生素治疗耗尽，表明肠道细菌可能参与餐后效应，我们的初步数据表明石胆酸（LCA）（肠道细菌产生的次级胆汁酸）可能是一种内源性抑制剂。 sEH，介导餐后 sEH 活性的调节该提案的另一个目的是验证涉及 LCA 的餐后 sEH 调节的新机制。因此，拟议的研究将探索体内 sEH 调节的新机制并评估我们新的性能。基于血浆氧脂素评估 sEH 活性的方法的成功完成将促进动物和人类体内 sEH 调节的研究，并带来新的治疗靶点或策略。治疗糖尿病或心血管疾病。