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Interaction of Ceramide Synthase with Long Chain Fatty Acyl‐CoA Synthase 5 Channels de novo Ceramide to Acylceramide Generation by Diacylglycerol Acyltransferase 2 on Lipid Droplets

The central molecule of the sphingolipid pathway, ceramide, has been shown to regulate multiple cellular responses including growth arrest, senescence, apoptosis and autophagy. Fatty acyl‐CoA (FA‐CoA) dependent ceramide generation is catalyzed by ceramide synthases in the de novo pathway. Importantly, six CerS isoforms displaying different preferences to generate ceramides with distinct fatty acyl chains have been identified. Currently, there is little insight into the regulation of the distinct CerS enzymes. In an approach aimed at defining interacting partners with CerSs, we found that that fatty acyl CoA synthase ACSL5 interacts with CerS. Contrary to our initial hypothesis, ACSL5 generated FA‐CoA was not a direct substrate utilized by CerS to generate ceramide as measured by LC/MS. Rather, ACSL5 generated FA‐CoA was utilized with de novo ceramide for the generation of acylceramides, poorly studied ceramide metabolites. Moreover, 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 DGAT2 and involves the formation of an ACSL5‐CerS‐DGAT2 complex on lipid droplets. In summary, this study identifies the molecular mechanism of a novel metabolic pathway of acylceramide generation and implicates the importance of this novel pathway in ceramide‐mediated apoptosis.