Impaired sphingolipid synthesis in the respiratory tract induces airway hyperreactivity.

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 Med

authors

Worgall TS,Veerappan A,Sung B,Kim BI,Weiner E,Bholah R,Silver RB,Jiang XC,Worgall S

doi

10.1126/scitranslmed.3005765

subject

Has Abstract

pub_date

2013-05-22 00:00:00

pages

186ra67

issue

186

eissn

1946-6234

issn

1946-6242

pii

5/186/186ra67

journal_volume

5

pub_type

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