Fatty Acid Auxotrophy in Drosophila Larvae Lacking SREBP
Kunte, Amit Sudhakar
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A rapid increase in size is a major characteristic of larval development in Drosophila melanogaster. Such growth presumably requires the concomitant production of membrane lipids and is also accompanied by a significant accumulation of neutral lipid stores. Growing larvae must accumulate fatty acids to permit the synthesis of these lipids. Interestingly, wild type Drosophila can grow in the complete absence of exogenous fatty acids. This dissertation reports the finding that a lipogenic transcription factor, dSREBP (Drosophila Sterol Regulatory Element Binding Protein), is essential for the maintenance of this prototrophy. Drosophila larvae lacking dSREBP demonstrate a profound growth deficit in the second instar and die before reaching third instar. This is accompanied by transcriptional deficits in fatty acid synthetic genes. The growth deficit and lethality can be reversed by supplementing the culture medium with fatty acids. The most effective fatty acid, oleate, rescues 80 percent of dSREBP mutants to adulthood. Thus, a lack of dSREBP renders larvae auxotrophic for fatty acids. A reporter system demonstrates that dSREBP is active in tissues known to be involved in lipid metabolism- the fat body, oenocytes and anterior midgut. Finally, as expected of an end-product inhibited metabolic pathway, dSREBP activity can be suppressed by dietary supplementation with lipids. Thus, the dSREBP pathway coordinates endogenous synthesis with the dietary provision of exogenous lipids. These results establish Drosophila as a viable model for the genetic study of the SREBP pathway and provide the first evidence that, at an organismal level, the essential role of the pathway is the accumulation of lipids. The auxotrophic mutants and other reagents described here should be useful tools for further study of the SREBP pathway in particular and fatty acid metabolism in general.