The mechanism and regulation of Seipin-mediated lipid droplet assembly

Seipin介导的脂滴组装机制及调控

• 批准号: BB/W015722/1
• 负责人: Pedro Carvalho
• 金额: $ 58.89万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW015722%2F1
• 关键词: mechanism; regulation; Seipin; mediated; lipid

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.

所有的细胞都进化出了储存能量的方法，从而使营养可用性波动的影响最小化。虽然储能能力具有明显的优势，但放松管制的能量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疾病的标志，如肥胖症，动脉粥样硬化或糖尿病。在大多数细胞中，能量以脂肪（或中性脂质）的形式储存在称为脂滴（LD）的专用细胞隔室中。LD几乎存在于每一个真核细胞中，在细胞脂质和能量代谢中发挥核心作用。尽管它们普遍存在且重要，但控制LD形成的过程仍不清楚。蛋白质在所有细胞事件中发挥作用，包括脂肪储存成LD的过程。这个过程在酵母、人类和植物中是相似的，并且在所有情况下都依赖于一种叫做Seipin的蛋白质。重要的是，人类Seipin的突变导致脂肪储存失调，并且通常在家族性脂肪营养不良和肌病患者中观察到。我们和其他人的先前工作表明，酵母和人类中的Seipin可以通过与脂肪分子结合来促进LD的包装，从而提高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，已经鉴定出另外的蛋白质结合Seipin并介导LD形成，但它们的作用模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及其结合伙伴如何介导脂肪包装成LD。本提案中描述的工作将提供关于LD形成的深入信息，最终可能指导处理人类病理学（如肥胖和脂肪代谢障碍）的新策略。