Effects of diet on oxylipins

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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.**