Abstract
The backbone of all sphingolipids (SLs) is a sphingoid long-chain base (LCB) to which a fatty acid is N-acylated. Considerable variability exists in the chain length and degree of saturation of both of these hydrophobic chains, and recent work has implicated ceramides with different LCBs and N-acyl chains in distinct biological processes; moreover, they may play different roles in disease states and possibly even act as prognostic markers. We now demonstrate that the half-life, or turnover rate, of ceramides containing diverse N-acyl chains is different. By means of a pulse-labeling protocol using stable-isotope, deuterated free fatty acids, and following their incorporation into ceramide and downstream SLs, we show that very-long-chain (VLC) ceramides containing C24:0 or C24:1 fatty acids turn over much more rapidly than long-chain (LC) ceramides containing C16:0 or C18:0 fatty acids due to the more rapid metabolism of the former into VLC sphingomyelin and VLC hexosylceramide. In contrast, d16:1 and d18:1 ceramides show similar rates of turnover, indicating that the length of the sphingoid LCB does not influence the flux of ceramides through the biosynthetic pathway. Together, these data demonstrate that the N-acyl chain length of SLs may not only affect membrane biophysical properties but also influence the rate of metabolism of SLs so as to regulate their levels and perhaps their biological functions.
Highlights
Sphingolipids (SLs) are important membrane components that have become the focus of great interest over the past couple of decades due to their roles in membrane structure, cellular signaling, and human disease [1]
The complexity of SL structures is becoming more apparent by advances in analytical mass spectrometry, along with significant progress in identifying most, if not all, of the enzymes related to SL metabolism or those that impinge upon SL metabolism [12]
Ceramide is generated by ceramide synthases [13, 14], of which six exist in mammals, each of which is defined by its use of specific fatty acyl CoAs for the generation of ceramides with defined N-acyl chain lengths
Summary
Sphingolipids (SLs) are important membrane components that have become the focus of great interest over the past couple of decades due to their roles in membrane structure, cellular signaling, and human disease [1]. Chain (VLC) ceramides, appear to play specific roles in diabetes [9, 10] and in CVD [11], in which LC ceramides are more deleterious than VLC ceramides. Ceramide is the basic building block of all complex SLs and consists of a sphingoid long-chain base (LCB) to which an FA is N-acylated. Despite significant advances in delineating SL structure and understanding how they are generated, little information is available about the metabolic fate of different SLs or their rate of turnover and flux through the biosynthetic pathway. We label SLs using stableisotope, deuterated FFAs and show that the length of the N-acyl chain affects the rate of ceramide turnover, whereas the length of the LCB has no effect
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