Seipin: A central lipid rheostat

Seipin is a conformationally flexible, oligomeric scaffold that regulates cellular lipid homeostasis beyond lipid droplet (LD) biogenesis. Seipin senses local lipid composition and membrane features to direct metabolic flux toward specific pathways and organelles. Its ring adopts multiple conformations, influenced by cofactors such as the LD assembly factor 1 and adipogenin, as well as lipid ligands including phosphatidic acid, diacylglycerol, and triacylglycerol, conferring broad functional versatility. Although seipin is an ER-resident protein primarily enriched at ER-LD junctions, a fraction relocates to mitochondria-associated membranes under specific metabolic conditions, where it regulates lipid synthesis, turnover, and local Ca2+ levels, thereby facilitating interorganelle communication and maintaining metabolic stability. Seipin dysfunction disrupts this multinodal regulation, causing lipid imbalance, organelle abnormalities, and a range of metabolic and neuronal disorders. We propose a unified model in which seipin functions as a multistate proteolipid regulatory hub: a rheostat whose structure and interactome dynamically adjust to control lipid pathway decisions in response to metabolic signals across organelle contact networks.