title: 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.
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA. tpw7@columbia.edu
authors.forename: Tilla S
authors.initials: TS
authors.lastname: Worgall
authors.forename: Arul
authors.initials: A
authors.lastname: Veerappan
authors.forename: Biin
authors.initials: B
authors.lastname: Sung
authors.forename: Benjamin I
authors.initials: BI
authors.lastname: Kim
authors.forename: Evan
authors.initials: E
authors.lastname: Weiner
authors.forename: Reshma
authors.initials: R
authors.lastname: Bholah
authors.forename: Randi B
authors.initials: RB
authors.lastname: Silver
authors.forename: Xian-Cheng
authors.initials: XC
authors.lastname: Jiang
authors.forename: Stefan
authors.initials: S
authors.lastname: Worgall
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000150:complications / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D005260:Female; D006706:Homeostasis / Q000187:drug effects; D008168:Lung / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D008274:Magnesium / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009093:Mucus / Q000378:metabolism; D011014:Pneumonia / Q000150:complications / Q000473:pathology; D051102:Serine C-Palmitoyltransferase / Q000378:metabolism; D013107:Sphingolipids / Q000096:biosynthesis*
chemical_list: D005229:Fatty Acids, Monounsaturated; D013107:Sphingolipids; D051102:Serine C-Palmitoyltransferase; D008274:Magnesium; C001996:thermozymocidin