Seipin Facilitates Triglyceride Flow to Lipid Droplet and Counteracts Droplet Ripening via Endoplasmic Reticulum Contact.

Seipin is an oligomeric integral endoplasmic reticulum (ER) protein involved in lipid droplet (LD) biogenesis. To study the role of seipin in LD formation, we relocalized it to the nuclear envelope and found that LDs formed at these new seipin-defined sites. The sites were characterized by uniform seipin-mediated ER-LD necks. At low seipin content, LDs only grew at seipin sites, and tiny, growth-incompetent LDs appeared in a Rab18-dependent manner. When seipin was removed from ER-LD contacts within 1 h, no lipid metabolic defects were observed, but LDs became heterogeneous in size. Studies in seipin-ablated cells and model membranes revealed that this heterogeneity arises via a biophysical ripening process, with triglycerides partitioning from smaller to larger LDs through droplet-bilayer contacts. These results suggest that seipin supports the formation of structurally uniform ER-LD contacts and facilitates the delivery of triglycerides from ER to LDs. This counteracts ripening-induced shrinkage of small LDs. • Seipin can determine the site of LD formation • Seipin-mediated ER-LD membrane contacts display a uniform neck-like architecture • Seipin at ER-LD contact facilitates continuous triglyceride transfer to LD • Acute removal of seipin reveals a principle of LD ripening via the ER Salo et al. show that seipin determines where a lipid droplet (LD) forms and establishes a neck between ER and LD. LDs continuously exchange lipids via ER, and biophysically, larger LDs acquire lipids more readily than smaller ones. Seipin facilitates lipid transfer to droplets, helping small LDs to grow. [ABSTRACT FROM AUTHOR]