Lipids
Myristate-derived d16:0 Sphingolipids Constitute a Cardiac Sphingolipid Pool with Distinct Synthetic Routes and Functional Properties*

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The enzyme serine palmitoyltransferase (SPT) catalyzes the formation of the sphingoid base “backbone” from which all sphingolipids are derived. Previous studies have shown that inhibition of SPT ameliorates pathological cardiac outcomes in models of lipid overload, but the metabolites responsible for these phenotypes remain unidentified. Recent in vitro studies have shown that incorporation of the novel subunit SPTLC3 broadens the substrate specificity of SPT, allowing utilization of myristoyl-coenzyme A (CoA) in addition to its canonical substrate palmitoyl-CoA. However, the relevance of these findings in vivo has yet to be determined. The present study sought to determine whether myristate-derived d16 sphingolipids are represented among myocardial sphingolipids and, if so, whether their function and metabolic routes were distinct from those of palmitate-derived d18 sphingolipids. Data showed that d16:0 sphingoid bases occurred in more than one-third of total dihydrosphingosine and dihydroceramides in myocardium, and a diet high in saturated fat promoted their de novo production. Intriguingly, d16-ceramides demonstrated highly limited N-acyl chain diversity, and in vitro enzyme activity assays showed that these bases were utilized preferentially to canonical bases by CerS1. Functional differences between myristate- and palmitate-derived sphingolipids were observed in that, unlike d18 sphingolipids and SPTLC2, d16 sphingolipids and SPTLC3 did not appear to contribute to myristate-induced autophagy, whereas only d16 sphingolipids promoted cell death and cleavage of poly(ADP-ribose) polymerase in cardiomyocytes. Thus, these results reveal a previously unappreciated component of cardiac sphingolipids with functional differences from canonical sphingolipids.

Cardiac Muscle
Cell Metabolism
Ceramide
Heart
Lipid Metabolism
Obesity
Sphingolipid
Ceramide Synthase
Serine Palmitoyltransferase

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*

This work was supported, in whole or in part, by National Institutes of Health (NIH), NIDDK, Grant F30DK092125 (to S.B.R.); NIH Grant P30 CA138313 (Lipidomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina (MUSC)); NIH Grant P20 RR017677 (Lipidomics Core in the South Carolina Lipidomics and Pathobiology Centers of Biomedical Research Excellence (COBRE), Department of Biochemistry, MUSC); and the NIH COBRE in Lipidomics and Pathobiology at MUSC (to L. A. C.). This work was also supported by a Merit Award from the Department of Veterans Affairs (to L. A. C.).

This article contains supplemental Fig. 1.

1

The Joseph Meyerhoff Professor of Biochemistry at the Weizmann Institute of Science.