The mechanism and regulation of Seipin-mediated lipid droplet assembly

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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.