Guo Yi, Walther Tobias C, Rao Meghana, Stuurman Nico, Goshima Gohta, Terayama Koji, Wong Jinny S, Vale Ronald D, Walter Peter, Farese Robert V
Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158, USA.
Nature. 2008 May 29;453(7195):657-61. doi: 10.1038/nature06928. Epub 2008 Apr 13.
Eukaryotic cells store neutral lipids in cytoplasmic lipid droplets enclosed in a monolayer of phospholipids and associated proteins. These dynamic organelles 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.
真核细胞将中性脂质储存在由单层磷脂和相关蛋白包裹的细胞质脂滴中。这些动态细胞器是储存细胞能量和膜脂构建块的主要场所。细胞内脂质过度积累是肥胖、糖尿病和动脉粥样硬化的核心特征，但令人惊讶的是，人们对脂滴细胞生物学知之甚少。在这里，我们通过在果蝇S2细胞中进行全基因组RNA干扰（RNAi）筛选表明，所有基因中约1.5%在脂滴形成和调控中发挥作用。基因敲低的表型分为五个不同的表型类别。编码磷脂生物合成酶的基因被证明是脂滴大小和数量的决定因素，这表明单层磷脂的组成深刻影响脂滴形态和脂质利用。Arf1-COPI囊泡运输蛋白的一个子集也调节脂滴形态和脂质利用，从而确定了该机制以前未被认识的功能。这些表型在哺乳动物细胞中是保守的，这表明这些研究的见解可能是我们理解涉及脂质过度储存的人类疾病的核心。
