title: Myristate-derived d16:0 sphingolipids constitute a cardiac sphingolipid pool with distinct synthetic routes and functional properties.
abstract: BACKGROUND
  Myristate is a novel potential substrate for sphingoid base synthesis.
  
  
  RESULTS
  Myocardial sphingoid base synthesis utilizes myristate; these sphingolipids are functionally non-redundant with canonical sphingoid bases.
  
  
  CONCLUSIONS
  d16:0 and d16:1 sphingolipids constitute an appreciable proportion of cardiac dihydrosphingosine and dihydroceramide, with distinct biological roles.
  
  
  CONCLUSIONS
  This pool of sphingolipids may play a heretofore unsuspected role in myocardial pathology or protection. 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29403, USA.
authors.forename: Sarah Brice
authors.initials: SB
authors.lastname: Russo
authors.forename: Rotem
authors.initials: R
authors.lastname: Tidhar
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Futerman
authors.forename: L Ashley
authors.initials: LA
authors.lastname: Cowart
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D053898:Biosynthetic Pathways; D002415:Cats; D002460:Cell Line; D002470:Cell Survival; D059305:Diet, High-Fat; D015870:Gene Expression; D015971:Gene Expression Regulation, Enzymologic; D006352:Heart Ventricles / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000201:enzymology; D009206:Myocardium / Q000166:cytology / Q000201:enzymology; D032383:Myocytes, Cardiac / Q000502:physiology; D019814:Myristic Acid / Q000378:metabolism*; D010171:Palmitoyl Coenzyme A / Q000378:metabolism; D051381:Rats; D051102:Serine C-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism*; D013107:Sphingolipids / Q000378:metabolism*; D051049:Sphingosine N-Acyltransferase / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D000214:Acyl Coenzyme A; D007527:Isoenzymes; D013107:Sphingolipids; D019814:Myristic Acid; D010171:Palmitoyl Coenzyme A; C040349:S-tetradecanoyl-coenzyme A; D051049:Sphingosine N-Acyltransferase; C582181:SPTLC3 protein, mouse; D051102:Serine C-Palmitoyltransferase; C495088:Sptlc1 protein, mouse
keywords: Cardiac Muscle; Cell Metabolism; Ceramide; Ceramide Synthase; Heart; Lipid Metabolism; Obesity; Serine Palmitoyltransferase; Sphingolipid