Myristate‐derived d16:0‐sphingolipids constitute an abundant cardiac sphingolipid pool with distinct synthetic routes and functional properties

Abstract

Previously, our laboratory demonstrated that sphingolipids (SL) mediated diet‐induced diabetic cardiomyopathy in mice (Russo et al. 2012. J Clin Invest). Intriguingly, affected hearts displayed accumulation of a novel pool of myristate‐derived d16:0 SL. However, the metabolism and biological functions of these lipids have yet to be defined. The present study sought to identify the metabolic routes through which these lipids were produced in the heart and to determine whether they were functionally distinct from canonical d18:0 SL. Data revealed that d16:0 SL were produced de novo within cardiomyocytes, comprised a major proportion of the cardiac simple SL pool, and increased in response to excess saturated fatty acids. Additionally, d16:0 and d18:0 SL were shown to be functionally distinct. In isolated adult cardiomyocytes, markers of apoptosis accumulated in response to increased d16:0 SL, but not d18:0 SL. In contrast, accumulation of d18:0 SL, but not d16:0 SL, promoted autophagy in these cells. Thus, these results reveal a previously unappreciated component of the cardiac sphingolipidome with functional differences from canonical sphingolipids.This work was supported by NIDDK F30DK092125 (to S.B.R.), a Merit Award from the Department of Veterans Affairs and the NIH COBRE in Lipidomics and Pathobiology (both to L.A.C.).