Effects of diet on oxylipins

氧脂素是多不饱和脂肪酸的生物活性产物，其在肾功能、血压控制、生殖、疼痛、炎症、凝血和许多其他方面具有许多生理作用。经典地，衍生自脂肪酸花生四烯酸（AA）的氧脂素被称为类二十烷酸，并且是氧脂素研究的主要焦点。然而，基于质谱仪的技术的最新应用已经将该领域从单个（或少数）类二十烷酸的研究带到了来自不同多不饱和脂肪酸的大量氧脂的同时分析。 由于氧化脂质是相互依赖的，并具有多种功能，分析氧化脂质的完整阵列是至关重要的脂肪酸功能的理解，通过他们的代谢氧化脂质。这种方法被用来研究许多氧化脂质衍生自AA，以及从二十碳五烯酸（EPA）和二十二碳六烯酸（DHA），这是ω-3脂肪酸常见于鱼油。 有趣的是，由饮食中的两种主要多不饱和脂肪酸，即亚油酸（LA）和α-亚麻酸（ALA）形成的氧脂素几乎完全未被探索。我们对LA和ALA衍生的氧脂素特别感兴趣，因为在我们之前的发现计划中，我们已经表明它们大量存在于动物组织中，它们具有与其他氧脂素相似的生物活性，并且饮食组成改变了这些氧脂素。 由于缺乏关于这些氧脂素的基本数据，该计划的第一个目标是表征组织中的氧脂素，并研究膳食脂肪酸组成如何影响组织氧脂素组成。这一点很重要，因为组织的氧脂素成分目前尚不清楚，我们已经证明，氧脂素成分并不总是反映脂肪酸成分。 第二个目的是进一步研究这些oxylipins的起源。抑制剂将用于鉴定主要LA和ALA氧脂素的氧脂素生物合成途径中的关键酶。在使用基因敲除小鼠确认这些发现后，将检查组织以确定这些途径在组织之间的差异以及饮食如何影响它们。 第三个目的是进一步探索饮食对氧脂素的影响。潜在的许多类型的饮食变化，可能会改变oxlipins，从而生理，我们建议检查组织oxlipins和它们的生物合成途径的饮食蛋白质水平的影响。 凭借我们在营养和氧脂素方面的独特专业知识，我们将提供有关组织中氧脂素形成的基础信息，以及两种不同的饮食操作如何影响这些氧脂素。这些基础知识将导致对脂肪酸组成文献的重新评估，并将适用于检查氧化脂质的许多生理作用的其他学科。

Oxylipins are biologically active products of polyunsaturated fatty acids that have numerous physiological roles in kidney function, blood pressure control, reproduction, pain, inflammation, blood clotting and many others. Classically, oxylipins derived from the fatty acid arachidonic acid (AA) have been called eicosanoids and were the main focus of oxylipin studies. However, recent application of mass spectrometer based technologies has taken the field from the study of individual (or a few) eicosanoids to the simultaneous analysis of large numbers of oxylipins from different polyunsaturated fatty acids. Since oxylipins are interdependent and have multiple functions, analysis of the complete array of oxylipins is critical to the understanding of fatty acid functions via their metabolism to oxylipins. This methodology is being used to study the many oxylipins derived from AA, as well as from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are omega-3 fatty acids commonly found in fish oils. Interestingly, the oxylipins formed from two main polyunsaturated fatty acids in the diet, namely linoleic (LA) and a-linolenic acid (ALA), are almost completely unexplored. We have a particular interest in the LA and ALA derived oxylipins because in our previous Discovery program we have shown that they are present in large amounts in animal tissues, they have bioactivity similar to the other oxylipins, and diet composition alters these oxylipins. Since basic data on these oxylipins is lacking, the first objective of the program is to characterize the oxylipins in tissues and to examine how dietary fatty acid composition influences tissue oxylipin composition. This is important because tissue oxylipin composition is currently unknown and we have shown that oxylipin composition does not always reflect fatty acid composition. The second objective is to further examine the origins of these oxylipins. Inhibitors will be used to identify the key enzymes in the oxylipin biosynthetic pathways for the major LA and ALA oxylipins. After confirming these findings by using knockout mice, tissues will be examined to determine how these pathways differ amongst tissues, and how diet affects them. The third objective is to further explore the effects of diet on oxylipins. Of the potentially many types of dietary changes that could alter oxylipins and thus physiology, we propose to examine the effect of dietary protein level on tissue oxylipins and their biosynthetic pathways. With our unique expertise in nutrition and oxylipins, we will therefore provide foundational information on oxylipin formation in tissues, and on how two diverse dietary manipulations can influence these oxylipins. This basic knowledge will result in re-evaluation of the fatty acid composition literature, and will be applicable to other disciplines that examine the many physiological roles of oxylipins.