The mechanism and regulation of Seipin-mediated lipid droplet assembly

所有的细胞都进化出了储存能量的方法，从而最大限度地减少了营养供应波动的影响。虽然能源储存的能力有明显的优势，但放松管制的能源积累也可能是有害的。事实上，过度的能量储存是西方世界一些最常见的疾病的标志，如肥胖、动脉粥样硬化或糖尿病。在大多数细胞中，能量以脂肪(或中性脂)的形式储存在一个称为脂滴(LD)的专用细胞隔室中。乳酸脱氢酶几乎存在于所有真核细胞中，在细胞脂代谢和能量代谢中发挥重要作用。尽管蛋白质的存在和重要性无处不在，但管理LDS形成的过程仍然不清楚。蛋白质在所有细胞活动中发挥作用，包括脂肪储存到LDS的过程。这一过程在酵母、人类和植物中都是相似的，在所有情况下都依赖于一种名为Seipin的蛋白质。重要的是，人类Seipin基因的突变会导致脂肪储存的紊乱，在有家族性脂肪营养不良和肌肉疾病的患者中通常可以观察到。我们和其他人之前的工作表明，酵母和人类中的Seipin可以通过与脂肪分子结合来促进LDS的包装，从而增加它们在LD形成部位的浓度。然而，Seipin如何在细胞环境中区分这些分子仍然是未知的。此外，还发现了更多与Seipin结合并介导LD形成的蛋白质，但它们的作用方式以及它们如何影响Seipin仍然是一个谜。在这里，我们的目标是确定Seipin及其结合伙伴如何将脂肪包装中介到LDS中。这项提案中描述的工作将提供关于LD形成的深入信息，最终可能指导应对肥胖和脂肪营养不良等人类病理的新策略。

All cells have evolved the means to store energy and thereby minimize the effects of fluctuations in nutrient availability. While the capability for energy storage has obvious advantages, deregulated energy accumulation can also be detrimental. Indeed, excessive energy storage is the hallmark of some of the most common diseases in the Western world such as obesity, atherosclerosis or diabetes.In most cells energy is stored as fat (or neutral lipids) in a dedicated cellular compartment called lipid droplet (LD). LDs are found in virtually every eukaryotic cell and play a central role in cellular lipid and energy metabolism. Despite their ubiquitous presence and importance, the processes governing the formation of LDs remain unclear.Proteins play a role in all cellular events, including the process of fat storage into LDs. This process is similar in yeast, human and plants and in all cases depends on a protein called Seipin. Importantly, mutations in human Seipin results in deregulated fat storage, and are commonly observed in patients with familial forms of lipodystrophies and myopathies.Previous work by us and others have suggested that Seipin in both yeast and humans can facilitate the packing of LDs by binding to fat molecules, thus raising their concentration at sites of LD formation. However, how Seipin distinguishes these molecules in the cellular environment remains unknown. Moreover, additional proteins have been identified to bind Seipin and mediate LD formation but their mode of action and how they influence Seipin is still a mystery. Here we aim to identify how Seipin and its binding partners mediate fat packaging into LDs. The work described in this proposal will offer in-depth information on LD formation that ultimately may guide to new strategies to deal with human pathologies such as obesity and lipodystrophies.