Effects of diet on oxylipins

氧磷脂是多不饱和脂肪酸的生物活性产物，在肾功能、血压控制、生殖、疼痛、炎症、凝血等许多方面具有广泛的生理作用。传统上，从脂肪酸花生四烯酸(AA)衍生出来的氧基脂被称为二十烷基类化合物，是氧基脂研究的主要焦点。然而，最近基于质谱仪的技术的应用已经将该领域从单个(或少数)二十烷基类化合物的研究带入同时分析不同多不饱和脂肪酸中大量氧脂的领域。由于氧脂是相互依赖的，并且具有多种功能，因此分析氧脂的完整序列对于了解其代谢成氧脂的脂肪酸功能是至关重要的。这种方法正被用于研究来自AA以及二十碳五烯酸(EPA)和二十二碳六烯酸(DHA)的许多氧化脂质，这些都是鱼油中常见的omega-3脂肪酸。*有趣的是，饮食中两种主要的多不饱和脂肪酸，即亚油酸(LA)和α-亚麻酸(ALA)形成的氧化脂质几乎完全没有被研究过。我们对LA和ALA衍生的氧脂特别感兴趣，因为在我们之前的探索计划中，我们已经证明它们在动物组织中大量存在，它们具有与其他氧脂相似的生物活性，而饮食组成改变了这些氧脂。*由于缺乏关于这些氧脂的基本数据，该计划的第一个目标是表征组织中的氧脂，并研究饮食脂肪酸组成如何影响组织氧脂组成。这一点很重要，因为组织氧脂组成目前尚不清楚，我们已经证明氧脂组成并不总是反映脂肪酸组成。*第二个目标是进一步研究这些氧脂的来源。抑制剂将被用来确定主要的LA和ALA氧脂生物合成途径中的关键酶。在用基因敲除小鼠确认这些发现后，将对组织进行检查，以确定这些途径在组织中的差异，以及饮食对它们的影响。*第三个目标是进一步探讨饮食对氧化脂质的影响。在许多可能改变氧脂从而改变生理学的饮食变化中，我们建议检查饮食蛋白质水平对组织氧脂及其生物合成途径的影响。*凭借我们在营养和氧脂方面的独特专业知识，我们将提供有关组织中氧脂形成的基础信息，以及两种不同的饮食操作如何影响这些氧脂。这一基本知识将导致对脂肪酸组成文献的重新评估，并将适用于其他研究氧脂的许多生理作用的学科。

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.**