The brown adipocyte protein CIDEA promotes lipid droplet fusion via a phosphatidic acid-binding amphipathic helix.
The brown adipocyte protein CIDEA promotes lipid droplet fusion via a phosphatidic acid-binding amphipathic helix.
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DOI：
10.7554/elife.07485
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发表时间：
2015-11-26
期刊：
影响因子：
7.7
通讯作者：
Christian M
中科院分区：
文献类型：
--
作者：
Barneda D;Planas-Iglesias J;Gaspar ML;Mohammadyani D;Prasannan S;Dormann D;Han GS;Jesch SA;Carman GM;Kagan V;Parker MG;Ktistakis NT;Klein-Seetharaman J;Dixon AM;Henry SA;Christian M
能量稳态的维持依赖于主要在脂肪组织中高度调节的三酰甘油的储存和释放，并且过度储存是常见代谢紊乱的特征。CIDEA是一种富含棕色脂肪细胞的脂滴（LD）蛋白，可促进LD的扩大，LD是一种动态的、普遍存在的细胞器，专门用于储存中性脂质。我们证明了一个重要的作用，在这个过程中的两亲性螺旋CIDEA，这有利于嵌入在LD磷脂单层和结合磷脂酸（PA）。LD对通过CIDEA反式复合物通过N-末端结构域和C-末端二聚化区域的贡献对接。这些复合物在LD-LD接触位点富集，与锥形磷脂PA相互作用，可能增加磷脂屏障通透性，通过脂质转移促进LD融合。这一生理过程对于脂肪细胞分化至关重要，并有助于促进活化棕色脂肪中脂肪分解和脂肪生成的紧密结合。http://dx.doi.org/10.7554/eLife.07485.001如果其他能量来源变得不可用，细胞就会依赖于称为脂质的脂肪分子的储存。这些被保存在细胞中被称为脂滴的膜封闭的隔间中，在哺乳动物中，脂滴在称为脂肪细胞的脂肪细胞中特别丰富。有两种主要类型的脂肪细胞：白色脂肪细胞有一个巨大的脂滴，而棕色脂肪细胞含有许多较小的液滴。包埋在脂质液滴周围的膜中的蛋白质有助于控制液滴的生长以及何时释放脂质。例如，一种名为CIDEA的蛋白质只存在于棕色脂肪细胞中，它通过使一个液滴将其内容物转移到另一个液滴来帮助脂滴生长。然而，很少有人知道这是如何发生的。通过结合细胞生物学、生物物理学和计算机建模方法，Barneda等人研究了CIDEA的正常和突变形式如何影响脂滴的生长。这些实验确定了CIDEA结构中的螺旋，该螺旋将其嵌入膜中，然后它可以与其他脂滴上的CIDEA蛋白相互作用，将液滴保持在一起。此外，螺旋与脂滴膜中称为磷脂酸的分子相互作用。Barneda等人认为，这种相互作用有助于将一个液滴的内容物转移到另一个液滴，使脂质更容易穿过液滴的膜。下一个挑战是表征控制CIDEA活性以影响多种脂滴形成的机制，这些脂滴将棕色和BRITE（白色中的棕色）脂肪细胞与白色脂肪细胞区分开来。棕色脂肪细胞中的脂滴是研究对抗肥胖的重要目标，因为这些细胞中发生的脂质“燃烧”而不是储存。DOI：http://dx.doi.org/10.7554/eLife.07485.002网站
Maintenance of energy homeostasis depends on the highly regulated storage and release of triacylglycerol primarily in adipose tissue, and excessive storage is a feature of common metabolic disorders. CIDEA is a lipid droplet (LD)-protein enriched in brown adipocytes promoting the enlargement of LDs, which are dynamic, ubiquitous organelles specialized for storing neutral lipids. We demonstrate an essential role in this process for an amphipathic helix in CIDEA, which facilitates embedding in the LD phospholipid monolayer and binds phosphatidic acid (PA). LD pairs are docked by CIDEA trans-complexes through contributions of the N-terminal domain and a C-terminal dimerization region. These complexes, enriched at the LD–LD contact site, interact with the cone-shaped phospholipid PA and likely increase phospholipid barrier permeability, promoting LD fusion by transference of lipids. This physiological process is essential in adipocyte differentiation as well as serving to facilitate the tight coupling of lipolysis and lipogenesis in activated brown fat. DOI: http://dx.doi.org/10.7554/eLife.07485.001 If other energy sources become unavailable, cells fall back on stores of fatty molecules called lipids. These are held in membrane-enclosed compartments in the cell called lipid droplets, which in mammals are particularly abundant in fat cells called adipocytes. There are two main types of adipocytes: white adipocytes have a single giant lipid droplet, whereas brown adipocytes contain many smaller droplets. Proteins embedded in the membrane that surrounds a lipid droplet help to control the droplet’s growth and when it releases lipids. For example, a protein called CIDEA, which is only found in brown adipocytes, helps lipid droplets to grow by enabling one droplet to transfer its contents to another droplet. However, little is known about how this occurs. By combining cell biology, biophysical and computer modelling approaches, Barneda et al. investigated how normal and mutant forms of CIDEA affect the growth of lipid droplets. These experiments identified a helix in the structure of CIDEA that embeds it in the membrane, from where it can then interact with CIDEA proteins on other lipid droplets to hold the droplets together. In addition, the helix interacts with a molecule in the lipid droplet membrane called phosphatidic acid. Barneda et al. suggest that this interaction helps to transfer the contents of one droplet to another by making it easier for lipids to move through the droplets’ membranes. The next challenge is to characterize the mechanisms that control CIDEA activity to influence the formation of the multiple lipid droplets that distinguish brown and BRITE (brown-in-white) adipocytes from white adipocytes. The lipid droplets in brown adipocytes are an important target for research to combat obesity, due to the 'burning' rather than storing of lipids that occurs in these cells. DOI: http://dx.doi.org/10.7554/eLife.07485.002