title: Ceramide Is Metabolized to Acylceramide and Stored in Lipid Droplets.
abstract: 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.
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Can E
authors.initials: CE
authors.lastname: Senkal
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Department of Biochemistry, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Dakahlia Governorate 35516, Egypt.
authors.forename: Mohamed F
authors.initials: MF
authors.lastname: Salama
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA; Northport Veterans Affairs Medical Center, Northport, NY 11768, USA.
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Snider
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Janet J
authors.initials: JJ
authors.lastname: Allopenna
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Nadia A
authors.initials: NA
authors.lastname: Rana
authors.affiliation: Proteomics Center, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Antonius
authors.initials: A
authors.lastname: Koller
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Yusuf A
authors.initials: YA
authors.lastname: Hannun
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA; Northport Veterans Affairs Medical Center, Northport, NY 11768, USA. Electronic address: lina.obeid@stonybrookmedicine.edu.
authors.forename: Lina M
authors.initials: LM
authors.lastname: Obeid
mesh_terms: D000215:Acylation; D000818:Animals; D002518:Ceramides / Q000378:metabolism*; D003066:Coenzyme A Ligases / Q000737:chemistry / Q000378:metabolism; D051048:Diacylglycerol O-Acyltransferase / Q000378:metabolism; D059305:Diet, High-Fat; D005247:Feeding Behavior; D020868:Gene Silencing; D045325:HCT116 Cells; D006801:Humans; D066292:Lipid Droplets / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008810:Mice, Inbred C57BL; D010088:Oxidoreductases / Q000378:metabolism; D000072417:Protein Domains; D013379:Substrate Specificity
chemical_list: D002518:Ceramides; D010088:Oxidoreductases; C108138:dihydroceramide desaturase; C494885:DGAT2 protein, human; D051048:Diacylglycerol O-Acyltransferase; D003066:Coenzyme A Ligases; C485465:ACSL5 protein, human
keywords: CerS; DGAT; acylceramide; apoptosis; ceramide; ceramide synthase; diacylglycerol acyltransferase; fatty acyl-CoA synthase; lipid droplets; sphingolipids