出版社：American Society for Biochemistry and Molecular Biology
摘要：Ceramide is a key bioactive mediator that inhibits surfactantphosphatidylcholine (PtdCho) synthesis in lung epithelia. Ceramideavailability is governed by sphingomyelin (SM) hydrolysis, butless is known regarding its de novo synthesis. In this study,we observed that ceramide synthesis within murine lung epitheliawas associated with high-level ceramide synthase (dihydroceramidesynthase) activity. Longevity assurance homolog 5 (LASS5) wasthe predominant ceramide synthase isoform detected in lung epithelia,whereas relatively lower level expression was detected for theother five mammalian homologs. Pulmonary LASS5 was developmentallyregulated, but its expression was spatially and gender nonspecific.Exogenously expressed LASS5 in lung epithelia was membrane-associated,triggering increased ceramide synthesis, whereas knockdown studiesusing fumonisin B1 or LASS5 small, interfering RNA reduced ceramidesynthase activity by 78% or 45%, respectively. Overexpressionof LASS5 also reduced PtdCho synthesis, but maximal inhibitionwas achieved when LASS5 was coexpressed with a plasmid encodinga neutral sphingomyelinase involved in SM hydrolysis.
These results demonstrate that LASS5 is the major ceramide synthasegene product involved in sphingolipid production that may alsoregulate PtdCho metabolism in pulmonary epithelia.Abbreviations: CCT, CTP:phosphocholine cytidylyltransferase; FB1, fumonisin B1; LASS1, longevity assurance homolog 1; PtdCho, phosphatidylcholine; siRNA, small interfering RNA; SM, sphingomyelin; SMase, sphingomyelinase; SPT, serine palmitoyltransferase; TNF-, tumor necrosis factor-Supplementary key words longevity assurance homolog 5 • dihydroceramide synthase • phosphatidylcholine
, tumor necrosis factor-
