Regulation of the stearoyl-CoA desaturase by dietary fatty acids

Hope College, Holland MI

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Abstract

PROJECT SUMMARY The stearoyl-CoA fatty acid desaturase, encoded by the OLE1 gene in the model organism Saccharomyces cerevisiae, produces mono-unsaturated fatty acids (UFAs) from saturated precursors. Its activity is relevant to heart disease, diabetes, obesity, and some cancers where regulation of lipid metabolism is compromised. The long-term goal of the proposed work is to gain a better understanding of the regulation of the stearoyl-CoA desaturase by dietary fatty acids. Cells regulate expression of OLE1 through the ER resident transcription factors Mga2p and Spt23p. These proteins are converted from an inactive p120 form to an active p90 form, which translocate into the nuclease and activate transcription of OLE1. While aspects of the regulation are understood, it is far from complete: What signal causes Mga2p and Spt23p to be switched from ?off? to ?on?? What proteins are involved in these processes? The overarching hypothesis of this work is that fed fatty acids are trafficked to internal membranes where protein sensors recognize and communicate the status of the membrane to the regulators of OLE1 gene expression. The objective of the proposed work will be to identify the signals and gene products that regulate expression of OLE1 and how they work. This objective will be accomplished by three specific aims: 1) Specific aim one is to identify genes, and their encoded proteins, responsible for regulation of OLE1 through recognition and/or localization of exogenous unsaturated fatty acid species. Through isolation of mutants defective in their response to dietary UFAs, components of this pathway will be identified. 2) Specific aim two is to evaluate the nature of the signal of unsaturated fatty acid abundance or suitability, as detected by the regulatory network. Because the wide variety of UFAs (e.g. number of double bonds, position of double bonds, chain length) can differentially contribute to the overall functionality of a membrane, the fatty acid composition of the cell will be modified and the effect on OLE1 gene expression will be examined. This will permit correlation of structural or physical properties of the fatty acids with regulatory effect. 3) Specific aim three is to determine the role of the newly identified proteins in the regulatory scheme of OLE1. Once the gene products that participate in the regulation of OLE1 have been identified, their role in the following will be characterized: trafficking of UFAs, transcriptional regulation, mRNA stability, protein activity regulation; and the possible interaction between these proteins and the MGA2 and SPT23 transcription factors. These studies will also provide undergraduate students an opportunity to participate in all aspects of a research project, from hypothesis generation, experimental design, data collection and analysis, to presentation of results to a scientific audience, while contributing to our fundamental understanding of the regulation of cellular lipid metabolism by fed fatty acids. This knowledge is essential to ultimately developing new drugs and diagnostic targets to treat the human diseases related to fatty acid metabolism dysfunction.