Ceramide Is Metabolized to Acylceramide and Stored in Lipid Droplets

In an approach aimed at defining interacting partners of ceramide synthases (CerSs), we found that fatty acyl-CoA synthase ACSL5 interacts with all CerSs. We demonstrate that ACSL5-generated FA-CoA was utilized with de novo ceramide for the generation of acylceramides, poorly studied ceramide metabolites. Functionally, inhibition of ceramide channeling to acylceramide enhanced accumulation of de novo ceramide and resulted in augmentation of ceramide-mediated apoptosis. Mechanistically, we show that acylceramide generation is catalyzed by diacylglycerol acyltransferase 2 (DGAT2) on lipid droplets. In summary, this study identifies a metabolic pathway of acylceramide generation and its sequestration in LDs in cells and in livers of mice on a high-fat diet. The study also implicates this pathway in ceramide-mediated apoptosis, and has implications in co-regulation of triglyceride and sphingolipid metabolisms. [Display omitted] •Ceramide synthases (CerSs) associate with fatty acyl-CoA synthase ACSL5•CerS-ACSL-DGAT catalyzes acylceramide generation from ceramide in lipid droplets•High-fat diet induces accumulation of acylceramides in liver lipid droplets•Acylceramide formation in lipid droplets acts as a storage for ceramide Senkal et al. identify a pathway whereby ceramide is converted to acylceramides by a CerS-ACSL-DGAT complex in lipid droplets for storage. These results raise interesting questions as to the metabolic interplay of TG/DAG and ceramide/acylceramide and the roles of ACSL5 and CerS in regulating these balances.