Abstract:
: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.
journal_name
Sci Transl Medjournal_title
Science translational medicineauthors
Worgall TS,Veerappan A,Sung B,Kim BI,Weiner E,Bholah R,Silver RB,Jiang XC,Worgall Sdoi
10.1126/scitranslmed.3005765subject
Has Abstractpub_date
2013-05-22 00:00:00pages
186ra67issue
186eissn
1946-6234issn
1946-6242pii
5/186/186ra67journal_volume
5pub_type
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