Genetic Regulation of Unsaturated Fatty Acid Composition in C. elegans

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Abstract
Delta-9 desaturases, also known as stearoyl-CoA desaturases, are lipogenic enzymes responsible for the generation of vital components of membranes and energy storage molecules. We have identified a novel nuclear hormone receptor, NHR-80, that regulates delta-9 desaturase gene expression in Caenorhabditis elegans. Here we describe fatty acid compositions, lifespans, and gene expression studies of strains carrying mutations in nhr-80 and in the three genes encoding delta-9 desaturases, fat-5, fat-6, and fat-7. The delta-9 desaturase single mutants display only subtle changes in fatty acid composition and no other visible phenotypes, yet the fat-5;fat-6;fat-7 triple mutant is lethal, revealing that endogenous production of monounsaturated fatty acids is essential for survival. In the absence of FAT-6 or FAT-7, the expression of the remaining desaturases increases, and this ability to compensate depends on NHR-80. We conclude that, like mammals, C. elegans requires adequate synthesis of unsaturated fatty acids and maintains complex regulation of the delta-9 desaturases to achieve optimal fatty acid composition. The ratio of saturated to unsaturated fatty acids has a profound affect on the fluidity and function of cellular membranes. Animals, plants, and microorganisms regulate the synthesis of unsaturated fatty acids during changing environmental conditions, as well as in response to dietary nutrients. In this paper the authors use a combination of genetic and biochemical approaches to address the regulation of unsaturated fatty acid synthesis in the roundworm Caenorhabditis elegans. They identify a new transcription factor, NHR-80, that activates the expression of genes encoding delta-9 fatty acid desaturases, the enzymes responsible for catalyzing the insertion of double bonds into saturated fatty acid chains. These unsaturated fatty acids are critical components of membranes, as well as fat storage molecules. Experiments presented here demonstrate that the worms require adequate synthesis of unsaturated fatty acids for survival and that they maintain intricate regulation of the three delta-9 desaturase genes in response to different nutrients. Abnormalities in lipid metabolism lead to obesity and diabetes in humans; this study contributes to our understanding of the regulation of this metabolic pathway.