Formation and metabolism of nitrated fatty acids

项目摘要 硝基脂肪酸(NO2-FA)是存在于动物和人类体内的内源性适应性信号介质 基础条件下的组织和体液。它们是在炎症部位形成的，最重要的是，作为一种 含亚硝酸盐和硝酸盐的膳食成分(如叶菜)与结合脂肪酸的相互作用 (例如，乳制品和植物种子)。NO2-FA是亲电性和多效性信号调制器，具有 在不同的病理条件下表现出保护作用。他们通过反应来发挥他们的信号作用 用靶蛋白激活NRF2和热休克蛋白表达，抑制核因子-κB和刺激性炎症 信号和相关的纤维化事件。在R0期间，我们发现了一组新的硝化 NO2-共轭亚麻酸(NO2-CLNA)存在于健康人的尿液中。这些脂质贡献了40%的 总的NO2-FA池，尽管西方饮食中存在有限的CLNA底物水平。这个 在生物条件下，CLNA显著的硝化产率和易硝化，在 人类，以及潜在的生物活动，突出了这一提议的价值。我们假设 CLNA的硝化是胃腔内的一种关键反应，它提供了新的代谢、保护和 对这些共轭脂肪酸有抗炎作用。我们将通过以下几点来检验这一假设 目标： 目的#1定义NO2-CLnA的形成和吸收。 目的#2定义新的生物活性NO2-CLNA的反应性、信号特性和代谢 通过定量和机械的研究，这项建议有可能改变CLA和CLNA 并展示了硝化作用在赋予这些共轭分子新的信号活动方面的积极作用 脂肪酸，影响我们如何理解这些饮食脂肪酸的药理学。

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.