The goal of this project is to determine how membrane lipids containing specific fatty acids influence hormonal responses, signal transduction and cellular function. The immediate objective is to investigate the role of myristic acid in these processes, with emphasis on the inositol phospholipids, diacylglycerol, and insulin action. This should provide additional insight into basic mechanisms involved in widespread diseases such as non-insulin dependent diabetes and obesity. Myristic acid functions in protein acylation, protein glycan anchors glycolipid second messengers, and the diacylglycerol generated in response to insulin. To fully understand the relationship of myristic acid to these processes, more information is needed about the metabolism of myristic acid. The central aim of this proposal is to completely define the factors that influence the formation, processing, turnover and subcellular distribution of myristic acid. Cell culture systems will be used in order to better delineate cause and effect relationships. These studies will be done with BC3H1 myoblasts, which produce diacylglycerol containing myristic acid in response to insulin. Factors influencing this response will be fully evaluated. To judge the generality of these responses, the formation of diacylglycerol containing myristic acid also will be evaluated in Y79 retinoblastoma cells exposed to insulin. In addition, the relationship of myristic acid to inositol phospholipid turnover will be examined in GH3 pituitary cells, a system that can be activated hormonally and exhibits a well characterized phosphatidylinositol cycle response. Finally, cell lines will be developed that are enriched with myristic acid. Following lipid characterization, functional studies will be done with these enriched cells in an attempt to accentuate metabolic and regulatory processes specifically influenced by myristic acid. This should make such processes more easily detectable, and possibly uncover new functional roles for myristic acid.
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