Submitted on January 3, 2005
Revised on March 15, 2005
Accepted on March 16, 2005
LASS5 is the predominant ceramide synthase isoform involved in de novo sphingolipid synthesis in lung epithelia
Zhiwei Xu, Jiming Zhou, Diann M. McCoy, and Rama K. Mallampalli
Internal Medicine, University of Iowa, Iowa City, IA 52242
Corresponding Author: rama-mallampalli{at}uiowa.edu
Ceramide is a key bioactive mediator that inhibits surfactant phosphatidylcholine (PtdCho) synthesis in lung epithelia. Ceramide availability is governed by sphingomyelin 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. LASS5 was the predominant ceramide synthase isoform detected in lung epithelia whereas relatively lower-level expression was detected for the other five mammalian homologues. 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 siRNA reduced ceramide synthase activity by 78% and 45%, respectively. Overexpression of LASS5 also reduced PtdCho synthesis, but maximal inhibition was achieved when LASS5 was co-expressed with a plasmid encoding a neutral sphingomyelinase involved in sphingomyelin hydrolysis. The results demonstrate that LASS5 is the major ceramide synthase gene product involved in sphingolipid production that may also regulate PtdCho metabolism in pulmonary epithelia.
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