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

• 批准号: 10377514
• 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
• 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/10377514
• 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; Lead; Lithocholic Acid; Liver; Measurable; Measures; Mediating; Metabolic; Metabolic Diseases; Metabolism; Methods; Oxides; Pathologic; Performance; Physiological; Plasma; Production; Rattus; Regulation; Research Personnel; Role; Sample Size; Secondary to; Testing; Time; Time Study; Tissues; base; 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

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（Epoxyeicosatrienoic Acids，ECOs）是一种对代谢和心血管健康有益的脂质介质。雌二醇和其他FFA环氧化物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。抑制sEH（其增加雌二醇）可改善代谢和CV健康，并被提议作为治疗糖尿病和CV疾病的有效策略。尽管sEH对健康很重要，但人们对sEH在体内的调节方式知之甚少，特别是在sEH难以研究的人类中，这主要是由于对表达sEH的个体组织的获取有限或缺乏适当的工具来评估sEH活性。在人类研究中，通常通过测量血液中FFA环氧-二醇比率来推断sEH活性。在血液中可以检测到多达15对FFA环氧化物-二醇。我们最近开发了一种新的方法来估计体内sEH活性，它结合了代谢组学测定和所有可测量的环氧-二醇对的同时分析。该方法“多指标同时分析”（SAMI）显著提高了检测sEH活性变化（或组间差异）的能力。这一点很重要，尤其是在人体研究中，因为增加的功效可以用更小的样本量检测治疗效果，从而降低成本。该提案的一个目的是评估我们的新代谢组学方法SAMI在检测动物在各种条件下sEH活性或EET代谢变化方面的性能，然后才能广泛应用于人体研究。使用SAMI，我们最近的研究表明，大鼠餐后sEH活性显著降低。有趣的是，这种效应在肠道细菌被抗生素治疗耗尽的动物中完全消除，表明肠道细菌可能参与了餐后效应。我们的初步数据表明，有趣的可能性，石胆酸（LCA），由肠道细菌产生的二级胆汁酸，可能是一种内源性抑制剂的sEH，介导餐后调节sEH活性。该提案的另一个目的是验证这种涉及LCA的餐后sEH调节的新机制。因此，拟议的研究将探索一种新的机制，在体内调节sEH和评估我们的新方法的性能，以评估基于血浆氧化脂质sEH活性。成功完成拟议的研究将促进动物和人类体内sEH调节的研究，并在糖尿病或CV疾病的治疗中产生新的治疗靶点或策略。