Seipin Governs caveolin-1 trafficking through modulating sphingolipid-glycerolipid balance

Dysregulation of caveolin-1 (CAV1), a core component of caveolae, causes pleiotropic disorders; yet, the mechanisms governing its trafficking remain poorly understood. Here, we show that the lipid droplet (LD) biogenesis factor seipin regulates CAV1 localization. Seipin deficiency in mice and HeLa cells resulted in the accumulation of saturated lipids and ceramides, thereby 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, indicating that saturated lipids' accumulation is the root cause. Conversely, blocking fatty acid synthase in seipin knockout cells restored proper CAV1 localization. Our findings suggest that seipin regulates lipid fluxes between glycerolipids and sphingolipids, which is critical for TGN integrity and CAV1 sorting.