ArticleThe Journal of biological chemistry2012
Neutral sphingomyelinase 2 deficiency increases hyaluronan synthesis by up-regulation of Hyaluronan synthase 2 through decreased ceramide production and activation of Akt.
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 33 papers.
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Who cites it
33 citing papers in PubMed, 49 citations in OpenAlex.
- Identification of Sphingosine Kinase 1 as a Novel Protein Regulated by High Molecular Weight Hyaluronan in Ovarian Cancer.Journal of cellular and molecular medicine · 2025Article
- Study on Moisturizing Effect of Dendrobium officinale, Sparassis crispa, and Their Compound Extracts.Journal of cosmetic dermatology · 2025Article
- Inhibition of sphingomyelinase attenuates diet - Induced increases in aortic stiffness.Journal of molecular and cellular cardiology · 2022Article
- Disruption of adipocyte HIF-1Acta pharmaceutica Sinica. B · 2022Article
- Matters of size: Roles of hyaluronan in CNS aging and disease.Ageing research reviews · 2021Review
- Regulatory role of mammalian target of rapamycin signaling in exosome secretion and osteogenic changes in smooth muscle cells lacking acid ceramidase gene.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2021Article
- Ganglioside GT1b increases hyaluronic acid synthase 2 via PI3K activation with TLR2 dependence in orbital fibroblasts from thyroid eye disease patients.BMB reports · 2021Article
- Unsaturated fatty acid-enriched extract from Hippophae rhamnoides seed reduces skin dryness through up-regulating aquaporins 3 and hyaluronan synthetases 2 expressions.Journal of cosmetic dermatology · 2021Article
- Angiostatic cues from the matrix: Endothelial cell autophagy meets hyaluronan biology.The Journal of biological chemistry · 2020Review
- The nSMase2/Smpd3 gene modulates the severity of muscular dystrophy and the emotional stress response in mdx mice.BMC medicine · 2020Article
- Mycosporine-like amino acids stimulate hyaluronan secretion by up-regulating hyaluronan synthase 2 via activation of the p38/MSK1/CREB/c-Fos/AP-1 axis.The Journal of biological chemistry · 2020Article
- Dietary inulin decreases circulating ceramides by suppressing neutral sphingomyelinase expression and activity in mice.Journal of lipid research · 2020Article
- Neutral Sphingomyelinase-2 (NSM 2) Controls T Cell Metabolic Homeostasis and Reprogramming During Activation.Frontiers in molecular biosciences · 2020Article
- In Human and Mouse Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism.International journal of molecular sciences · 2019Article
- The Role of Ceramide and Sphingosine-1-Phosphate in Alzheimer's Disease and Other Neurodegenerative Disorders.Molecular neurobiology · 2019Review
- The Cross-Talk Between Sphingolipids and Insulin-Like Growth Factor Signaling: Significance for Aging and Neurodegeneration.Molecular neurobiology · 2019Review
- Role of Neutral Sphingomyelinase-2 (NSM 2) in the Control of T Cell Plasma Membrane Lipid Composition and Cholesterol Homeostasis.Frontiers in cell and developmental biology · 2019Article
- Sphingolipids and lipid rafts: Novel concepts and methods of analysis.Chemistry and physics of lipids · 2018Review
- nSMase2 (Type 2-Neutral Sphingomyelinase) Deficiency or Inhibition by GW4869 Reduces Inflammation and Atherosclerosis in ApoeArteriosclerosis, thrombosis, and vascular biology · 2018Article
- Increased liver tumor formation in neutral sphingomyelinase-2-deficient mice.Journal of lipid research · 2018Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Fibroblasts from the fro/fro mouse, with a deletion in the Smpd3 gene coding for the active site of neutral sphingomyelinase 2 (NSMase2), secreted increased amounts of hyaluronan (HA). This was reversed by transfection with the Smpd3 gene, suggesting a connection between sphingolipid and glycosaminoglycan metabolism. The deficiency of NSMase2 resulted in storage of sphingomyelin (SM) and cholesterol with a 50% reduction in ceramides (Cer). RT-PCR and Western blot analysis showed that increased HA secretion resulted from increased hyaluronan synthase 2 (HAS2) activity localized to sphingolipid-enriched lipid rafts. Although cholesterol levels were also elevated in lipid rafts from mouse fibroblasts deficient in lysosomal acid SMase activity (deletion of the Smpd1(-/-) gene), there was no increase in HA secretion. We then showed that in fro/fro fibroblasts, the reduced ceramide was associated with decreased phosphorylation of protein phosphatase 2A (PP2A) and increased phosphorylation of its substrate Akt-p, together with PI3K, PDK1, mTOR (mammalian target of rapamycin), and p70S6K, although PTEN was unaffected. Exogenous ceramide, as well as inhibitors of Akt (Akt inhibitor VIII), PI 3-kinase (LY294002 and wortmannin), and mTOR (rapamycin) reduced secretion of HA, whereas the NSMase2 inhibitor GW4869 increased HA synthesis and secretion. We propose that NSMase2/Cer are the key mediators of the regulation of HA synthesis, via microdomains and the Akt/mTOR pathway.
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