Beller Mathias, Sztalryd Carole, Southall Noel, Bell Ming, Jäckle Herbert, Auld Douglas S, Oliver Brian
Laboratory of Cellular and Developmental Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
PLoS Biol. 2008 Nov 25;6(11):e292. doi: 10.1371/journal.pbio.0060292.
Lipid droplets are ubiquitous triglyceride and sterol ester storage organelles required for energy storage homeostasis and biosynthesis. Although little is known about lipid droplet formation and regulation, it is clear that members of the PAT (perilipin, adipocyte differentiation related protein, tail interacting protein of 47 kDa) protein family coat the droplet surface and mediate interactions with lipases that remobilize the stored lipids. We identified key Drosophila candidate genes for lipid droplet regulation by RNA interference (RNAi) screening with an image segmentation-based optical read-out system, and show that these regulatory functions are conserved in the mouse. Those include the vesicle-mediated Coat Protein Complex I (COPI) transport complex, which is required for limiting lipid storage. We found that COPI components regulate the PAT protein composition at the lipid droplet surface, and promote the association of adipocyte triglyceride lipase (ATGL) with the lipid droplet surface to mediate lipolysis. Two compounds known to inhibit COPI function, Exo1 and Brefeldin A, phenocopy COPI knockdowns. Furthermore, RNAi inhibition of ATGL and simultaneous drug treatment indicate that COPI and ATGL function in the same pathway. These data indicate that the COPI complex is an evolutionarily conserved regulator of lipid homeostasis, and highlight an interaction between vesicle transport systems and lipid droplets.
脂滴是能量储存稳态和生物合成所需的普遍存在的甘油三酯和固醇酯储存细胞器。尽管对脂滴的形成和调控了解甚少，但很明显，PAT（围脂滴蛋白、脂肪细胞分化相关蛋白、47 kDa尾部相互作用蛋白）蛋白家族的成员覆盖在脂滴表面，并介导与重新动员储存脂质的脂肪酶的相互作用。我们通过基于图像分割的光学读出系统进行RNA干扰（RNAi）筛选，鉴定了果蝇中脂滴调控的关键候选基因，并表明这些调控功能在小鼠中是保守的。其中包括囊泡介导的衣被蛋白复合体I（COPI）转运复合体，它是限制脂质储存所必需的。我们发现COPI组分调节脂滴表面的PAT蛋白组成，并促进脂肪细胞甘油三酯脂肪酶（ATGL）与脂滴表面的结合以介导脂肪分解。已知两种抑制COPI功能的化合物Exo1和布雷菲德菌素A，模拟了COPI基因敲除的效果。此外，RNAi抑制ATGL并同时进行药物处理表明COPI和ATGL在同一途径中发挥作用。这些数据表明COPI复合体是脂质稳态的进化保守调节因子，并突出了囊泡运输系统与脂滴之间的相互作用。
