Impaired sphingolipid synthesis in the respiratory tract induces airway hyperreactivity Academic Article uri icon


MeSH Major

  • Bronchial Hyperreactivity
  • Lung
  • Sphingolipids


  • Asthma is a clinically heterogeneous genetic disease, and its pathogenesis is incompletely understood. Genome-wide association studies link ORM (yeast)-Like protein isoform 3 [corrected] (ORMDL3), a member of the ORM gene family, to nonallergic childhood-onset asthma. Orm proteins negatively regulate sphingolipid (SL) synthesis by acting as homeostatic regulators of serine palmitoyl-CoA transferase (SPT), the rate-limiting enzyme of de novo SL synthesis, but it is not known how SPT activity or SL synthesis is related to asthma. The present study analyzes the effect of decreased de novo SL synthesis in the lung on airway reactivity after administration of myriocin, an inhibitor of SPT, and in SPT heterozygous knockout mice. We show that, in both models, decreased de novo SL synthesis increases bronchial reactivity in the absence of inflammation. Decreased SPT activity affected intracellular magnesium homeostasis and altered the bronchial sensitivity to magnesium. This functionally links decreased de novo SL synthesis to asthma and so identifies this metabolic pathway as a potential target for therapeutic interventions.

publication date

  • May 22, 2013



  • Academic Article



  • eng

Digital Object Identifier (DOI)

  • 10.1126/scitranslmed.3005765

PubMed ID

  • 23698380

Additional Document Info

start page

  • 186ra67


  • 5


  • 186