Effects of diet on oxylipins

氧化脂素是多不饱和脂肪酸的生物活性产物，在肾脏功能、血压控制、生殖、疼痛、炎症、血液凝固等方面具有许多生理作用。传统上，从脂肪酸花生四烯酸（AA）中提取的氧化脂类被称为类二十烷，是氧化脂类研究的主要焦点。然而，近年来基于质谱技术的应用已经使该领域从单个（或少数）类二十烷化合物的研究发展到同时分析来自不同多不饱和脂肪酸的大量氧化脂类。******由于氧化脂类相互依赖且具有多种功能，因此分析完整的氧化脂类阵列对于了解脂肪酸通过其代谢为氧化脂类的功能至关重要。这种方法被用于研究从AA以及二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）中提取的许多氧脂类，这两种脂肪酸是鱼油中常见的-3脂肪酸。******有趣的是，由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）形成的氧脂素几乎完全没有被研究过。我们对LA和ALA衍生的氧化脂类特别感兴趣，因为在我们之前的发现项目中，我们已经证明它们在动物组织中大量存在，它们具有与其他氧化脂类相似的生物活性，而饮食成分会改变这些氧化脂类。******由于缺乏关于这些氧脂质的基本数据，该计划的第一个目标是表征组织中的氧脂质，并检查膳食脂肪酸组成如何影响组织中的氧脂质组成。这是很重要的，因为组织的氧脂质组成目前是未知的，我们已经表明氧脂质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化脂质的起源。抑制剂将用于识别主要LA和ALA氧化脂素生物合成途径中的关键酶。在通过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之间的差异，以及饮食如何影响它们。******第三个目标是进一步探索饮食对氧化脂质的影响。在可能改变氧脂素及其生理的多种饮食变化中，我们建议研究饮食蛋白质水平对组织氧脂素及其生物合成途径的影响。******凭借我们在营养和氧化脂类方面的独特专业知识，我们将提供组织中氧化脂类形成的基础信息，以及两种不同的饮食操作如何影响这些氧化脂类。这些基本知识将导致脂肪酸组成文献的重新评估，并将适用于其他学科，以检查许多生理作用的氧化脂素

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.**