COPI complex is a regulator of lipid homeostasis.
COPI complex is a regulator of lipid homeostasis.
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DOI：
10.1371/journal.pbio.0060292
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发表时间：
2008-11-25
期刊：
影响因子：
9.8
通讯作者：
Oliver B
中科院分区：
文献类型：
--
作者：
Beller M;Sztalryd C;Southall N;Bell M;Jäckle H;Auld DS;Oliver B
脂滴是普遍存在的甘油三酯和甾醇酯储存细胞器，其是能量储存稳态和生物合成所需的。虽然对脂滴的形成和调节知之甚少，但很明显PAT（perilipin，脂肪细胞分化相关蛋白，47 kDa的尾部相互作用蛋白）蛋白家族的成员包覆液滴表面并介导与脂肪酶的相互作用，所述脂肪酶使储存的脂质再活化。我们确定了关键的果蝇候选基因的脂滴调节RNA干扰（RNAi）筛选与图像分割为基础的光学读出系统，并表明，这些监管功能是保守的小鼠。这些包括囊泡介导的外壳蛋白复合物I（COPI）转运复合物，其是限制脂质储存所需的。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）与脂滴表面的缔合以介导脂解。已知抑制COPI功能的两种化合物，Exo 1和Brefeldin A，表型COPI敲低。此外，ATGL的RNAi抑制和同时的药物治疗表明COPI和ATGL在相同的途径中起作用。这些数据表明，COPI复合物是一种进化上保守的调节脂质稳态，并强调囊泡运输系统和脂滴之间的相互作用。脂肪细胞和一般细胞将脂肪酸转化为甘油三酯，储存在液滴中供将来使用。尽管脂滴在肥胖和其他疾病过程中具有巨大的重要性，但我们对液滴中的脂质储备如何形成以及这些储备如何减少知之甚少。我们已经使用模式果蝇果蝇来识别脂质储存和利用的候选调节因子，并且已经表明这些候选调节因子中的许多具有在哺乳动物中保守的功能。我们把注意力集中在一个囊泡运输途径，我们表明是必需的调节和酶的蛋白质在脂滴表面上发现的类型的调制。用RNA干扰或小分子化合物干扰这种运输系统的功能，会改变脂质储存。对这种新途径的理解，以及我们使用的特定试剂，可能最终导致新的治疗方法。在果蝇和哺乳动物细胞中，一个特定的囊泡运输机器被证明是细胞使用储存的脂质所必需的。
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. Fat cells, and cells in general, convert fatty acids into triglycerides that are stored in droplets for future use. Despite the enormous importance of lipid droplets in obesity and other disease processes, we know very little about how lipid reserves in droplets are formed and how those reserves are drawn down. We have used the model fruit fly Drosophila to identify candidate regulators of lipid storage and utilization, and have shown that many of these candidates have functions that are conserved in mammals. We focused our attention on a vesicle-trafficking pathway that we show is required for the modulation of the types of regulatory and enzymatic proteins found on the lipid droplet surface. Interfering with the function of this trafficking system with either RNA interference or small-molecule compounds alters lipid storage. The understanding of this new pathway, as well as the specific reagents we used, may ultimately lead to new therapeutics. A specific vesicle-trafficking machine is shown to be required for cells to use stored lipid, in bothDrosophila and mammalian cells.
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影响因子：
7.7
作者：
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