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.

项目总结