Formation and metabolism of nitrated fatty acids

硝化脂肪酸的形成和代谢

• 批准号: 10796440
• 负责人: Francisco Jose Schopfer
• 金额: $ 11.75万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-10 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10796440
• 关键词: Anti-Inflammatory Agents; Biological; Consumption; Dairy Products; Dietary Component; Dietary Fatty Acid; Disease; Event; Fatty Acids; Food; Heat shock proteins; Human; Inflammation; Inflammatory; Linolenic Acids; Lipids; Liquid substance; Mediator; Metabolic; Metabolic Diseases; Metabolism; Nitrates; Nitrites; Nitrogen Dioxide; Pathologic; Pharmacology; Plants; Property; Proteins; Reaction; Role; Signal Transduction; Site; Stomach; Testing; Urine; Vegetables; absorption; animal tissue; dietary approach; dietary nitrate; human tissue; nitration; protective effect; protein expression; western diet

Project Summary Nitro-fatty acids (NO2-FA) are endogenous adaptive signaling mediators present in animal and human tissues and fluids under basal conditions. They are formed at sites of inflammation and, most importantly, as an interaction of dietary components containing nitrite and nitrate (e.g. leafy vegetables) and conjugated fatty acids (e.g. dairy products, and plant seeds). NO2-FA are electrophilic and pleiotropic signaling modulators that have demonstrated protective effects in various pathological conditions. They exert their signaling actions by reacting with target proteins to activate Nrf2 and heat shock protein expression, inhibit NF-κB and STING inflammatory signaling, and associated fibrotic events. During the R0, we discovered the presence of a new group of nitrated species, NO2-conjugated linolenic acid (NO2-CLNA), in healthy human urines. These lipids contribute to 40% of the total NO2-FA pool, despite the limited levels of the CLNA substrate present in the western diet. The remarkable nitration yields and ease of nitration of CLNA under biological conditions, the levels detected in humans, and the potential biological activities underscore the value of this proposal. We hypothesize that the nitration of CLNA is a critical reaction in the gastric compartment that confers new metabolic, protective, and anti-inflammatory functions to these conjugated fatty acids. We will test the hypothesis through the following Aims: Aim #1 Define the NO2-CLnA formation and absorption. Aim #2 Define the reactivity, signaling properties, and metabolism of new bioactive NO2-CLNA Through quantitative and mechanistic studies, this proposal has the potential to change the CLA and CLNA paradigm and demonstrate an active role for nitration in conferring new signaling activities to these conjugated fatty acids, impacting how we understand pharmacology of these dietary fatty acids.

项目概要 硝基脂肪酸 (NO2-FA) 是存在于动物和人类中的内源性适应性信号传导介质 它们是在基础条件下的组织和液体中形成的，最重要的是，它们是作为一种物质而形成的。 含有亚硝酸盐和硝酸盐的膳食成分（例如叶类蔬菜）与共轭脂肪酸的相互作用 （例如乳制品和植物种子）。NO2-FA 是具有亲电性和多效性的信号调节剂。 他们通过反应证明了其在各种病理条件下的保护作用。 与靶蛋白结合，激活Nrf2和热休克蛋白表达，抑制NF-κB和STING炎症 在 R0 期间，我们发现了一组新的硝基化事件的存在。 健康人尿液中的 40% 是由 NO2 结合亚麻酸 (NO2-CLNA) 组成。 尽管西方饮食中存在的 CLNA 底物水平有限，但 NO2-FA 总量仍然存在。 CLNA 在生物条件下具有显着的硝化产率和硝化容易度，检测到的水平 人类及其潜在的生物活动强调了该提案的价值。 CLNA 的硝化是胃室中的一个关键反应，它赋予新的代谢、保护和 这些共轭脂肪酸的抗炎功能我们将通过以下方式检验该假设。 目标： 目标#1 定义 NO2-CLnA 的形成和吸收。 目标 #2 定义新生物活性 NO2-CLNA 的反应性、信号传导特性和代谢 通过定量和机制研究，该提案有可能改变 CLA 和 CLNA 范式并证明硝化在赋予这些共轭物新的信号活性方面发挥积极作用 脂肪酸，影响我们如何理解这些膳食脂肪酸的药理学。