FISH OIL HYDROXY FATTY ACIDS AS CELLULAR MODULATORS

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Epidemiological evidence suggests that diets rich in fish oil lipids are associated with decreased incidence of coronary vascular disease. The exact mechanisms through which these special dietary components produce the observed results are unknown but a number of studies indicate that n-3 polyunsaturated fatty acids (PUFAs) derived from fish may modulate arachidonic acid metabolism leading to leukotrienes, prostanoids and other biologically active products. Although the n-3 PUFAs could directly interfere with the formation of n-6 eicosanoids, another attractive hypothesis is that metabolism of n-3 PUFAs produces certain products which are the actual modulators of various metabolic processes. When PUFAs are metabolized by cellular lipoxygenases, monohydroxy fatty acids (HOFAs) are usually the most abundant products formed. We, as well as other groups, have found that HOFAs derived from arachidonic acid (HETEs) regulate a variety of biological responses and processes. It is the objective of this proposal to evaluate the biological properties of several HOFAs derived from fish oil n-3 PUFAs. We propose to synthesize six different fish oil HOFAs (FHOFAs) from eicosapentaenoic acid and docosahexaenoic acid and to examine the regulatory effects of these FHOFAs on various enzymes that release and metabolize arachidonic acid including platelet and neutrophil phospholipases, cyclooxygenases and lipoxygenases. Cells will be isolated from human and rat donors on normal diets as well as from donors whose diets will be supplemented with fish oil in order to determine whether the cellular lipid content influences the modulatory properties of the FHOFAs. We will also investigate how readily these FHOFAs are incorporated into cellular lipids and whether these FHOFAs are chemotactic for PMNs, influence calcium homeostasis and platelet and neutrophil aggregation. It is hoped that these studies will provide new insights into the mechanisms through which n-3 PUFAs, present in seafoods, influence certain metabolic processes. In addition, the results from the proposed studies could suggest new strategies for the treatment and/or prevention of inflammatory and cardiovascular diseases.