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.

项目摘要 硝基脂肪酸（NO2-FA）是动物和人类中存在的内源性自适应信号传导介质 基本条件下的组织和流体。它们是在炎症部位形成的，最重要的是 含有亚硝酸盐和硝酸盐（例如叶蔬菜）和共轭脂肪酸的饮食成分的相互作用 （例如乳制品和植物种子）。 NO2-FA是具有电力和多效信号调节器的 在各种病理条件下证明了受保护的作用。他们通过反应发挥信号动作 靶蛋白激活NRF2和热激蛋白表达，抑制NF-κB和刺激性 信号传导和相关的纤维化事件。在R0期间，我们发现了一组新的硝化 健康的人类尿液中的NO2偶联的亚麻酸（NO2-CLNA）物种。这些脂质贡献了40％ 总NO2-FA池，在西部饮食中进行有限的CLNA底物水平。这 在生物条件下，明显的硝化产率和CLNA的硝化易应性，在 人类以及潜在的生物学活动强调了这一提议的价值。我们假设 CLNA的硝化是胃室中的关键反应，供认新的代谢，受保护和 这些共轭脂肪酸的抗炎功能。我们将通过以下来检验假设 目标： 目标＃1定义了NO2-CLNA的形成和遗憾。 AIM＃2定义了新生物活性NO2-CLNA的反应性，信号传导特性和代谢 通过定量和机械研究，该建议有可能改变CLA和CLNA 范式并证明了硝化作用在为这些共轭的新信号活动中发挥作用 脂肪酸，影响我们如何理解这些饮食脂肪酸的药理学。