Seipin Governs Caveolin-1 Trafficking Through Modulating Sphingolipid-Glycerolipid Balance

Dysregulation of Caveolin-1 (CAV1), a key component of caveolae, leads to pleiotropic disorders; yet, the mechanisms controlling its trafficking remain unclear. Here, we show that the lipid droplet (LD) biogenesis factor seipin controls CAV1 localization. Seipin deficiency in mice and HeLa cells resulted in the accumulation of saturated lipids and ceramides, disrupting the membrane order of the trans-Golgi network (TGN). This impaired CAV1 trafficking to the plasma membrane, reduced caveolae formation, and redirected CAV1 to LDs - an effect also observed in seipin-deficient patient fibroblasts. We reproduced this phenotype in wild-type cells by supplementing them with palmitate or ceramide, or by inhibiting stearoyl-CoA desaturase 1, which suggests that accumulating saturated lipids are the root cause. Inhibiting fatty acid synthase in seipin knockout cells rescued CAV1 localization. Our findings indicate that seipin modulates lipid partitioning between glycerolipids and sphingolipids, which is critical for maintaining TGN function in CAV1 sorting and trafficking.