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 在基础条件下的组织和液体。它们形成于炎症部位，最重要的是， 含亚硝酸盐和硝酸盐的膳食成分（例如多叶蔬菜）与共轭脂肪酸的相互作用 (e.g.乳制品和植物种子）。NO2-FA是亲电性和多效性信号调节剂， 在各种病理条件下表现出保护作用。它们通过反应来发出信号 用靶蛋白激活Nrf 2和热休克蛋白的表达，抑制NF-κB和STING炎症反应 信号传导和相关的纤维化事件。在R 0期间，我们发现了一组新的硝化 NO2-共轭亚麻酸（NO2-CLNA）。这些脂质占40%， 尽管西方饮食中存在的CLNA底物水平有限，但总NO2-FA库。的 显着的硝化产率和易于硝化的CLNA在生物条件下，检测到的水平， 人类和潜在的生物活动强调了这一建议的价值。我们假设 CLNA的硝化是胃隔室中的关键反应，其赋予新的代谢、保护和 这些共轭脂肪酸的抗炎功能。我们将通过以下方式来检验这个假设 目的： 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、信号传导特性和代谢 通过定量和机理研究，该方案具有改变CLA和CLNA的潜力 范例，并证明硝化在赋予这些共轭的新的信号传导活性中的积极作用。 脂肪酸，影响我们如何理解这些膳食脂肪酸的药理学。

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.