Species-level ceramide sources based on CERS enzyme expression profile and substrate specificity. Ceramide synthases, the step in the de novo synthesis pathway that adds a variable acyl chain to the sphingoid backbone, result in much of the diversity of the sphingolipid pool. Varied tissue expression and substrate selectivity result in unique tissue distributions of ceramide species. The circulating ceramide pool reflects the tissue distribution of the CERS enzymes and their substrate preferences. Abbreviations: CERS1–6, ceramide synthases 1–6; VLDL, very-low-density lipoprotein; LDL, low-density lipoprotein; HDL, high-density lipoprotein; sEV, small extracellular vesicle).