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Journal of Lipid Research, Vol. 46, 1229-1238, June 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

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^1,*,,

^* Departments of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242
Biochemistry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242
Department of Veterans Affairs Medical Center, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242

Published, JLR Papers in Press, March 16, 2005. DOI 10.1194/jlr.M500001-JLR200

¹ To whom correspondence should be addressed. e-mail: 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 (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.

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

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				Y. Pewzner-Jung, S. Ben-Dor, and A. H. Futerman When Do Lasses (Longevity Assurance Genes) Become CerS (Ceramide Synthases)?: INSIGHTS INTO THE REGULATION OF CERAMIDE SYNTHESIS J. Biol. Chem., September 1, 2006; 281(35): 25001 - 25005. [Full Text] [PDF]

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