ArticleThe Journal of biological chemistry2012
Mammalian ORMDL proteins mediate the feedback response in ceramide biosynthesis.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 90 papers.
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Who cites it
90 citing papers in PubMed, 149 citations in OpenAlex.
- ORMDL Proteins Turnover via Proteasome and Autophagy Is Cell-Type Dependent and Tied to Ceramide Homeostasis.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Functional profiling and visualization of the sphingolipid metabolic network in vivo.EMBO reports · 2025Article
- The individual isoforms of ORMDL, the regulatory subunit of serine palmitoyltransferase, have distinctive sensitivities to ceramide.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2025Article
- Intricate Regulation of Sphingolipid Biosynthesis: An In-Depth Look Into ORMDL-Mediated Regulation of Serine Palmitoyltransferase.BioEssays : news and reviews in molecular, cellular and developmental biology · 2025Review
- Multi-Omic Profiling Identifies Conserved Metabolic Pathways Critical for SARS-CoV-2 Variants Infection.bioRxiv : the preprint server for biology · 2025Article
- Advances in ORMDL Research in Malignant Tumors: A Review.OncoTargets and therapy · 2025Review
- Targeting ORMDL2 in glioblastoma through integrated landscape of high-throughput sequencing and pharmacogenomic analysis.International journal of medical sciences · 2025Article
- Atypical sphingosine-1-phosphate metabolites-biological implications of alkyl chain length.Pflugers Archiv : European journal of physiology · 2024Review
- Functional and Molecular Characterization of NewGenes · 2024Article
- Multi-Omics Reveals Disrupted Immunometabolic Homeostasis and Oxidative Stress in Adipose Tissue of Dairy Cows with Subclinical Ketosis: A Sphingolipid-Centric Perspective.Antioxidants (Basel, Switzerland) · 2024Article
- Proteomics analysis of plasm exosomes in early pregnancy among normal pregnant women and those with antiphospholipid syndrome.Heliyon · 2024Article
- ORMDL3 regulates NLRP3 inflammasome activation by maintaining ER-mitochondria contacts in human macrophages and dictates ulcerative colitis patient outcome.The Journal of biological chemistry · 2024Article
- SPTLC2 variants are associated with early-onset ALS and FTD due to aberrant sphingolipid synthesis.Annals of clinical and translational neurology · 2024Article
- Sphingolipid classes and the interrelationship with pediatric asthma and asthma risk factors.Allergy · 2024Article
- Recurrent de novoJournal of neurology, neurosurgery, and psychiatry · 2024Article
- Three kingdoms and one ceramide to rule them all. A comparison of the structural basis of ceramide-dependent regulation of sphingolipid biosynthesis in animals, plants, and fungi.Advances in biological regulation · 2024Article
- Fine-tuned protein-lipid interactions in biological membranes: exploration and implications of the ORMDL-ceramide negative feedback loop in the endoplasmic reticulum.Frontiers in cell and developmental biology · 2024Article
- Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders.Journal of neuromuscular diseases · 2024Review
- The Implication of Sphingolipids in Viral Infections.International journal of molecular sciences · 2023Review
- Sphingolipids in Childhood Asthma and Obesity (SOAP Study): A Protocol of a Cross-Sectional Study.Metabolites · 2023Article
30 more citing papers are in PubMed but not listed here.
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe yeast Orm1/2 proteins regulate ceramide biosynthesis.
resultsDepletion of the mammalian Orm1/2 homologues, ORMDL1-3, eliminates the negative feedback of exogenous ceramide on ceramide biosynthesis in HeLa cells.
conclusionORMDL proteins are the primary regulators of ceramide biosynthesis in mammalian cells. SIGNIFICANCE: Therapeutically manipulating levels of the pro-death lipid, ceramide, requires a molecular understanding of its regulation. The mammalian ORMDL proteins are orthologues of the yeast Orm proteins (Orm1/2), which are regulators of ceramide biosynthesis. In mammalian cells, ceramide is a proapoptotic signaling sphingolipid, but it is also an obligate precursor to essential higher order sphingolipids. Therefore levels of ceramide are expected to be tightly controlled. We tested the three ORMDL isoforms for their role in homeostatically regulating ceramide biosynthesis in mammalian cells. Treatment of cells with a short chain (C6) ceramide or sphingosine resulted in a dramatic inhibition of ceramide biosynthesis. This inhibition was almost completely eliminated by ORMDL knockdown. This establishes that the ORMDL proteins mediate the feedback regulation of ceramide biosynthesis in mammalian cells. The ORMDL proteins are functionally redundant. Knockdown of all three isoforms simultaneously was required to alleviate the sphingolipid-mediated inhibition of ceramide biosynthesis. The lipid sensed by the ORMDL-mediated feedback mechanism is medium or long chain ceramide or a higher order sphingolipid. Treatment of permeabilized cells with C6-ceramide resulted in ORMDL-mediated inhibition of the rate-limiting enzyme in sphingolipid biosynthesis, serine palmitoyltransferase. This indicates that C6-ceramide inhibition requires only membrane-bound elements and does not involve diffusible proteins or small molecules. We also tested the atypical sphingomyelin synthase isoform, SMSr, for its role in the regulation of ceramide biosynthesis. This unusual enzyme has been reported to regulate ceramide levels in the endoplasmic reticulum. We were unable to detect a role for SMSr in regulating ceramide biosynthesis. We suggest that the role of SMSr may be in the regulation of downstream metabolism of ceramide.
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