Abstract
Ceramide is a key bioactive mediator that inhibits surfactant phosphatidylcholine (PtdCho) synthesis in lung epithelia. Ceramide availability is governed by sphingomyelin (SM) hydrolysis, but less is known regarding its de novo synthesis. In this study, we observed that ceramide synthesis within murine lung epithelia was associated with high-level ceramide synthase (dihydroceramide synthase) activity. Longevity assurance homolog 5 (LASS5) was the predominant ceramide synthase isoform detected in lung epithelia, whereas relatively lower level expression was detected for the other five mammalian homologs. Pulmonary LASS5 was developmentally regulated, but its expression was spatially and gender nonspecific. Exogenously expressed LASS5 in lung epithelia was membrane-associated, triggering increased ceramide synthesis, whereas knockdown studies using fumonisin B1 or LASS5 small, interfering RNA reduced ceramide synthase activity by 78% or 45%, respectively. Overexpression of LASS5 also reduced PtdCho synthesis, but maximal inhibition was achieved when LASS5 was coexpressed with a plasmid encoding a neutral sphingomyelinase involved in SM hydrolysis. These results demonstrate that LASS5 is the major ceramide synthase gene product involved in sphingolipid production that may also regulate PtdCho metabolism in pulmonary epithelia.
Highlights
Ceramide is a key bioactive mediator that inhibits surfactant phosphatidylcholine (PtdCho) synthesis in lung epithelia
Compared with labeling within sphingosine, SM, or sphingosine-1-phosphate, both MLE cells and type II cells synthesized large amounts of ceramide from sphingosine independent of the duration of pulse labeling. These results demonstrate that murine lung epithelia predominantly synthesize ceramide from sphingolipid precursors using a de novo pathway
The primary aim of this study was to ascertain whether ceramide, generated via a de novo pathway, coordinately inhibits PtdCho production in lung epithelia
Summary
Ceramide is a key bioactive mediator that inhibits surfactant phosphatidylcholine (PtdCho) synthesis in lung epithelia. Overexpression of LASS5 reduced PtdCho synthesis, but maximal inhibition was achieved when LASS5 was coexpressed with a plasmid encoding a neutral sphingomyelinase involved in SM hydrolysis. These results demonstrate that LASS5 is the major ceramide synthase gene product involved in sphingolipid production that may regulate PtdCho metabolism in pulmonary epithelia.—Xu, Z., J. Prior studies have demonstrated that ceramides are metabolically derived, in part, from sphingomyelin (SM) hydrolysis [9] In this pathway, one of several membraneassociated sphingomyelinases (SMases) catalyze the rapid hydrolysis of SM to ceramide in response to a physiologic stress signal.
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