Functional genomic screen reveals genes involved in lipid-droplet formation and utilization
Functional genomic screen reveals genes involved in lipid-droplet formation and utilization
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DOI：
10.1038/nature06928
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发表时间：
2008-05-29
期刊：
影响因子：
64.8
通讯作者：
Farese, Robert V., Jr.
中科院分区：
文献类型：
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作者：
Guo, Yi;Walther, Tobias C.;Farese, Robert V., Jr.
真核细胞将中性脂储存在细胞质脂滴中（1,2），脂滴包裹在磷脂和相关蛋白的单层中（3,4）。这些动态细胞器(5)是储存细胞能量的主要储存库，也是膜脂的组成部分。细胞中过度的脂质积累是肥胖、糖尿病和动脉粥样硬化的中心特征，然而关于脂滴细胞生物学的了解却非常少。通过在果蝇S2细胞中进行全基因组RNA干扰（RNAi）筛选，我们发现约1.5%的基因参与脂滴的形成和调控。基因敲低的表型分为五个不同的表型类。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地影响了脂滴的形态和脂质的利用。Arf1 - COPI囊泡转运蛋白的一个子集也调节液滴形态和脂质利用，从而确定了这一机制的一个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，这表明来自这些研究的见解可能是我们理解涉及过度脂质储存的人类疾病的核心。
Eukaryotic cells store neutral lipids in cytoplasmic lipid droplets(1,2) enclosed in a monolayer of phospholipids and associated proteins(3,4). These dynamic organelles(5) 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.