ORMDL/serine palmitoyltransferase stoichiometry determines effects of ORMDL3 expression on sphingolipid biosynthesis

Deanna Siow, Manjula Sunkara, Teresa M. Dunn, Andrew J. Morris, Binks Wattenberg

Research output: Contribution to journalArticlepeer-review

46 Scopus citations


The ORM1 (Saccharomyces cerevisiae)-like proteins (ORMDLs) and their yeast orthologs, the Orms, are negative homeostatic regulators of the initiating enzyme in sphingolipid biosynthesis, serine palmitoyltransferase (SPT). Genome-wide association studies have established a strong correlation between elevated expression of the endoplasmic reticulum protein ORMDL3 and risk for childhood asthma. Here we test the notion that elevated levels of ORMDL3 decrease sphingolipid biosynthesis. This was tested in cultured human bronchial epithelial cells (HBECs) (an immortalized, but untransformed, airway epithelial cell line) and in HeLa cells (a cervical adenocarcinoma cell line). Surprisingly, elevated ORMDL3 expression did not suppress de novo biosynthesis of sphingolipids. We determined that ORMDL is expressed in functional excess relative to SPT at normal levels of expression. ORMDLs and SPT form stable complexes that are not increased by elevated ORMDL3 expression. Although sphingolipid biosynthesis was not decreased by elevated ORMDL3 expression, the steady state mass levels of all major sphingolipids were marginally decreased by low level ORMDL3 over-expression in HBECs. These data indicate that the contribution of ORMDL3 to asthma risk may involve changes in sphingolipid metabolism, but that the connection is complex.

Original languageEnglish
Pages (from-to)898-908
Number of pages11
JournalJournal of Lipid Research
Issue number4
StatePublished - Apr 1 2015

Bibliographical note

Publisher Copyright:
© 2015, American Society for Biochemistry and Molecular Biology Inc. All rights reserved.


  • Asthma
  • Ceramides
  • Endoplasmic reticulum
  • Enzymology/enzyme regulation
  • Lung
  • ORM1 (saccharomyces cerevisiae)-like protein
  • Orm
  • Sphingosine phosphate

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology


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