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Sphingolipids, ORMDL3 and asthma: what is the evidence?

Tilla S Worgall1

  • 1Columbia University Medical Center, New York City, New York, USA.

Current Opinion in Clinical Nutrition and Metabolic Care
|December 29, 2016
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ORMDL3, an endoplasmic reticulum protein, is linked to asthma risk. Studies suggest it affects asthma by altering sphingolipid synthesis and potentially impacting airway smooth muscle contraction, influencing disease severity and persistence.

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Area of Science:

  • Immunology
  • Genetics
  • Biochemistry

Background:

  • Genome-wide association studies identify ORMDL3 as a significant asthma risk factor.
  • ORMDL3 is involved in maintaining sphingolipid homeostasis.
  • Asthma pathogenesis is complex, involving genetic and environmental factors.

Purpose of the Study:

  • To summarize potential mechanisms by which increased ORMDL3 expression contributes to asthma.
  • To investigate the role of ORMDL3 in sphingolipid metabolism and its relation to airway hyperreactivity.
  • To explore the impact of ORMDL3 on allergic asthma models and sphingolipid profiles.

Main Methods:

  • Investigated effects of decreased sphingolipid synthesis using genetic models and myriocin.
  • Examined ORMDL3 expression and its impact in allergic asthma models (ovalbumin, house dust mites, Alternaria alternata).
  • Analyzed ORMDL3 knockout mice and sphingolipid profiles in relation to asthma persistence.

Main Results:

  • Decreased sphingolipid synthesis alone can induce airway hyperreactivity (AHR).
  • Overexpression of ORMDL3 increases inflammatory markers, airway remodeling, and AHR in allergic models.
  • ORMDL3 knockout mice are protected from Alternaria-induced AHR, suggesting a role in smooth muscle contraction.
  • Sphingolipid profiles, specifically ceramides, may predict asthma persistence in children.

Conclusions:

  • ORMDL3 may affect asthma through sphingolipid synthesis inhibition and synergistic effects with allergens.
  • ORMDL3 plays a role in allergic airway hyperreactivity and smooth muscle contraction.
  • Sphingolipid profiles may serve as biomarkers for asthma persistence.