ArticleThe Journal of biological chemistry2015
Coordinated regulation of the orosomucoid-like gene family expression controls de novo ceramide synthesis in mammalian cells.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 43 citations in OpenAlex.
- Sphingolipids and Atherosclerosis.Current atherosclerosis reports · 2026Review
- Advances in ORMDL Research in Malignant Tumors: A Review.OncoTargets and therapy · 2025Review
- Development of Genetically Encoded Fluorescent KSR1-Based Probes to Track Ceramides during Phagocytosis.International journal of molecular sciences · 2024Article
- Simultaneous reduction of all ORMDL proteins decreases the threshold of mast cell activation.Scientific reports · 2023Article
- ORMDL in metabolic health and disease.Pharmacology & therapeutics · 2023Review
- Sphingolipids and Asthma.Advances in experimental medicine and biology · 2022Article
- ORMDL3 Functions as a Negative Regulator of Antigen-Mediated Mast Cell ActivationFrontiers in immunology · 2021Article
- Increasing Sphingolipid Synthesis Alleviates Airway Hyperreactivity.American journal of respiratory cell and molecular biology · 2020Article
- Review
- Differential Expression of Ormdl Genes in the Islets of Mice and Humans with Obesity.iScience · 2020Article
- Article
- Expression Patterns and Prognostic Values of ORMDL1 in Different Cancers.BioMed research international · 2020Article
- The ORMDL3 asthma susceptibility gene regulates systemic ceramide levels without altering key asthma features in mice.The Journal of allergy and clinical immunology · 2019Article
- Trafficking of Stretch-Regulated TRPV2 and TRPV4 Channels Inferred Through Interactomics.Biomolecules · 2019Review
- Aryl hydrocarbon receptor signaling promotes ORMDL3-dependent generation of sphingosine-1-phosphate by inhibiting sphingosine-1-phosphate lyase.Cellular & molecular immunology · 2019Article
- ORMDL3 and allergic asthma: From physiology to pathology.The Journal of allergy and clinical immunology · 2019Review
- Ceramide Imbalance and Impaired TLR4-Mediated Autophagy in BMDM of an ORMDL3-Overexpressing Mouse Model.International journal of molecular sciences · 2019Article
- ER Stress and the UPR in Shaping Intestinal Tissue Homeostasis and Immunity.Frontiers in immunology · 2019Review
- Orm/ORMDL proteins: Gate guardians and master regulators.Advances in biological regulation · 2018Review
- Sphingolipid biosynthesis in man and microbes.Natural product reports · 2018Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The orosomucoid-like (ORMDL) protein family is involved in the regulation of de novo sphingolipid synthesis, calcium homeostasis, and unfolded protein response. Single nucleotide polymorphisms (SNPs) that increase ORMDL3 expression have been associated with various immune/inflammatory diseases, although the pathophysiological mechanisms underlying this association are poorly understood. ORMDL proteins are claimed to be inhibitors of the serine palmitoyltransferase (SPT). However, it is not clear whether individual ORMDL expression levels have an impact on ceramide synthesis. The present study addressed the interaction with and regulation of SPT activity by ORMDLs to clarify their pathophysiological relevance. We have measured ceramide production in HEK293 cells incubated with palmitate as a direct substrate for SPT reaction. Our results showed that a coordinated overexpression of the three isoforms inhibits the enzyme completely, whereas individual ORMDLs are not as effective. Immunoprecipitation and fluorescence resonance energy transfer (FRET) studies showed that mammalian ORMDLs form oligomeric complexes that change conformation depending on cellular sphingolipid levels. Finally, using macrophages as a model, we demonstrate that mammalian cells modify ORMDL genes expression levels coordinately to regulate the de novo ceramide synthesis pathway. In conclusion, we have shown a physiological modulation of SPT activity by general ORMDL expression level regulation. Moreover, because single ORMDL3 protein alteration produces an incomplete inhibition of SPT activity, this work argues against the idea that ORMDL3 pathophysiology could be explained by a simple on/off mechanism on SPT activity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.