1. Department of Biochemistry and Biophysics,
2. Department of Cellular and Molecular Pharmacology, and,
3. Department of Medicine, University of California, San Francisco, California 94158, USA
4. Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA
5. Max-Planck Institute of Biochemistry, D-12852 Martinsried, Germany
6. Howard Hughes Medical Institute, University of California, San Francisco, California 94158-2517, USA
7. These authors contributed equally to this work.
8. Present address: Institute for Advanced Research, Nagoya University, 464-8601 Nagoya, Japan.

Correspondence to: Tobias C. Walther^1,5,7Robert V. Farese^1,3,4 Correspondence and requests for materials should be addressed to R.F. (Email: bfarese@gladstone.ucsf.edu) or T.W. (Email: twalther@biochem.mpg.de).

Abstract

Eukaryotic cells store neutral lipids in cytoplasmic lipid droplets^{1, 2} enclosed in a monolayer of phospholipids and associated proteins^{3, 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.

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