CERAMIDE IS METABOLIZED TO ACYLCERAMIDE AND STORED IN LIPID DROPLETS

SUMMARY

In an approach aimed at defining interacting partners of ceramide synthases (CerS), we found that fatty acyl CoA synthase ACSL5 interacts with all CerS. 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 LD in cells and in livers of mice on a high fat diet. The study also implicates this novel pathway in ceramide-mediated apoptosis, and has implications in co-regulation of triglyceride and sphingolipid metabolisms.

eTOC Blurb

XXX et al identify a novel 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.