Functional genomic screen reveals genes involved in lipid-droplet formation and utilization

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Abstract
Lipid droplets are found in nearly all eukaryotic cells and contain neutral lipids such as triacylglycerols and sterol esters. There is rapidly growing interest in the cell biology of lipid storage, largely due to the central role that these processes play in obesity and related metabolic diseases. Guo et al. have performed a genome-wide RNA interference screen in Drosophila cells and identify genes involved in lipid droplet formation and utilization. About 1.5% of all genes are involved in these processes. Eukaryotic cells store neutral lipids in cytoplasmic lipid droplets. Processes regulating the formation of these organelles are at present unknown. A genome-wide RNAi screen in Drosophila cells identifies genes involved in lipid droplet formation and utilization, finding that 1% of all genes are involved in these processes. This study will lead to an understanding of human diseases involving excessive lipid storage. Eukaryotic cells store neutral lipids in cytoplasmic lipid droplets1,2 enclosed in a monolayer of phospholipids and associated proteins3,4. These dynamic organelles5 serve as the principal reservoirs for storing cellular energy and for the building blocks for membrane lipids. Excessive lipid accumulation in cells is a central feature of obesity, diabetes and atherosclerosis, yet remarkably little is known about lipid-droplet cell biology. Here we show, by means of a genome-wide RNA interference (RNAi) screen in Drosophila S2 cells that about 1.5% of all genes function in lipid-droplet formation and regulation. The phenotypes of the gene knockdowns sorted into five distinct phenotypic classes. Genes encoding enzymes of phospholipid biosynthesis proved to be determinants of lipid-droplet size and number, suggesting that the phospholipid composition of the monolayer profoundly affects droplet morphology and lipid utilization. A subset of the Arf1–COPI vesicular transport proteins also regulated droplet morphology and lipid utilization, thereby identifying a previously unrecognized function for this machinery. These phenotypes are conserved in mammalian cells, suggesting that insights from these studies are likely to be central to our understanding of human diseases involving excessive lipid storage.