The Use of Genetic Approach to Optimize Essential Fatty Acid Composition

摘要

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are essential components required for normal cellular function and have been shown to exert many preventive and therapeutic actions. The amount of n-3 PUFAs is insufficient in most people, whereas the level of n-6 PUFAs is relatively too high with an n-6-3 ratio of >15. These two classes of PUFAs are metabolically and functionally distinct and often have important opposing physiological functions; their balance is important for good health and normal development. However, mammalian cells cannot convert n-6 to n-3 PUFAs because they lack the converting enzyme n-3 desaturase. Thus, the only way to enrich the tissues with n-3 PUFAs in mammals so far has been dietary provision of n-3 PUFAs. Recently, a fat-1 gene encoding an n-3 fatty acid desaturase that is able to convert n-6 fatty acids to corresponding n-3 PUFAs has been cloned from C. elegans. On this basis, we have explored the feasibility of optimizing mammalian essential fatty acid profile by converting the excessive n-6 fatty acids to n-3 fatty acids using gene transfer of the C. elegans n-3 desaturase. Our results showed that adenovirus-mediated introduction of the C. elegans fat-1 gene into mammalian cells (including heart cells, neurons, endothelial cells and human breast cancer cells) could quickly and effectively elevate the cellular n-3 PUFA contents and dramatically balance the ratio of n-6-3 PUFAs (from about 10-15:1 to 1:1). In addition, the eicosanoids derived from n-6 PUFAs were significantly reduced in the transgenic cells. Accordingly, these gene transfer-mediated changes in lipid profiles exerted beneficial effects on cell function, similar to or even better than those induced by supplementation with exogenous n-3 PUFA. Our studies demonstrate a novel and effective approach to optimizing fatty acid composition of mammalian cells and also provide a basis for potential applications of this gene transfer in gene therapy as well as in production of n-3 fatty acid-enriched meat and milk in animals.