Increased Levels of Sphingosylphosphorylcholine (SPC) in Plasma of Metabolic Syndrome Patients

El‐Najjar, Nahed; Orsó, Evelyn; Wallner, Stefan; Liebisch, Gerhard; Schmitz, Gerd

doi:10.1371/journal.pone.0140683

Cited by 19 publications

(10 citation statements)

References 56 publications

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“…SPC also fosters proinflammatory events in cerebral arteries, 58,60 contributing to progression of atherosclerosis and cardiovascular events. High plasma levels of SPC are associated with metabolic syndrome, 43 which is still 1 major risk factor for cardiovascular diseases and thrombo-occlusive disorders. Thus, SPC could be useful as antiplatelet therapy in thrombo-occlusive diseases.…”

Section: Discussionmentioning

confidence: 99%

“…SPC was highly upregulated (by a factor of 10) in SMPD1-deficient platelets to give a final concentration of 20 mM ( Figure 6A-B), which is 800-fold higher than the concentration found in human plasma (25 nM). 43 Other SL lipids, such as So (sphingosine) and Sa (sphinganine), were simultaneously decreased, indicating a shift in SL metabolism toward SPC ( Figure 6B-C).…”

Section: Impact Of Smpd1 On the Platelet Lipidomementioning

confidence: 99%

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Identification of key lipids critical for platelet activation by comprehensive analysis of the platelet lipidome

Peng

Geue²,

Coman

et al. 2018

Blood

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Platelet integrity and function critically depend on lipid composition. However, the lipid inventory in platelets was hitherto not quantified. Here, we examined the lipidome of murine platelets using lipid-category tailored protocols on a quantitative lipidomics platform. We could show that the platelet lipidome comprises almost 400 lipid species and covers a concentration range of 7 orders of magnitude. A systematic comparison of the lipidomics network in resting and activated murine platelets, validated in human platelets, revealed that <20% of the platelet lipidome is changed upon activation, involving mainly lipids containing arachidonic acid. Sphingomyelin phosphodiesterase-1 (Smpd1) deficiency resulted in a very specific modulation of the platelet lipidome with an order of magnitude upregulation of lysosphingomyelin (SPC), and subsequent modification of platelet activation and thrombus formation. In conclusion, this first comprehensive quantitative lipidomic analysis of platelets sheds light on novel mechanisms important for platelet function, and has therefore the potential to open novel diagnostic and therapeutic opportunities.

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Section: Discussionmentioning

confidence: 99%

Section: Impact Of Smpd1 On the Platelet Lipidomementioning

confidence: 99%

Identification of key lipids critical for platelet activation by comprehensive analysis of the platelet lipidome

Peng

Geue²,

Coman

et al. 2018

Blood

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“…Possibly, the metabolic block affects the global degradation pathway of sphingolipids. Several other factors could be responsible for LysoSLs unspecific increases: cationic amphiphilic drugs like amiodarone can induce lipidosis [ 31 ]; LysoSM can also be elevated in the plasma of patients with metabolic syndrome [ 48 ], and a lowering effect of oral contraceptives on LysoHexCer was recently described [ 27 ]. These elevations however are moderate when compared to those observed in sphingolipidoses and NPC.…”

Section: Discussionmentioning

confidence: 99%

LC-MS/MS multiplex analysis of lysosphingolipids in plasma and amniotic fluid: A novel tool for the screening of sphingolipidoses and Niemann-Pick type C disease

Pettazzoni¹,

Froissart²,

Pagan³

et al. 2017

PLoS ONE

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BackgroundThe biological diagnosis of sphingolipidoses currently relies on the measurement of specific enzymatic activities and/or genetic studies. Lysosphingolipids have recently emerged as potential biomarkers of sphingolipidoses and Niemann-Pick type C in plasma.MethodologyWe developed a sensitive and specific method enabling the simultaneous quantification of lysosphingolipids by LC-MS/MS: lysoglobotriaosylceramide for Fabry disease, lysohexosylceramide (i.e. lysoglucosylceramide and/or lysogalactosylceramide) for Gaucher and Krabbe diseases, lysosphingomyelin and its carboxylated analogue lysosphingomyelin-509 for Niemann-Pick type A or B, and C diseases, lysoGM1 ganglioside for GM1gangliosidosis and lysoGM2 ganglioside for GM2 gangliosidosis.FindingsThe diagnostic performances were validated in plasma samples analysing a large series of patients affected with sphingolipidoses and Niemann-Pick type C disease (n = 98), other inborn errors of metabolism (n = 23), and controls (n = 228). The multiplex measurement of lysosphingolipids allowed the screening of Fabry (including female patients and late-onset variants), Gaucher and infantile Krabbe, Niemann-Pick type A/B and C diseases with high sensitivity and specificity. LysoGM1 and LysoGM2 were elevated in most of the patients affected with GM1 and GM2 gangliosidosis respectively.In amniotic fluid supernatant from pregnancies presenting non-immune hydrops fetalis (n = 77, including previously diagnosed Gaucher (n = 5), GM1 gangliosidosis (n = 4) and galactosialidosis (n = 4) fetuses) and from normal pregnancies (n = 15), a specific and dramatic increase of lysohexosylceramide was observed only in the Gaucher amniotic fluid samples.InterpretationThis multiplex assay which allows the simultaneous measurement of lysosphingolipids in plasma modifies the diagnostic strategy of sphingolipidoses and Niemann-Pick type C. Furthermore, in pregnancies presenting non-immune hydrops fetalis, lysohexosylceramide measurement in amniotic fluid offers a rapid screening of fetal Gaucher disease without waiting for glucocerebrosidase activity measurement in cultured amniocytes.

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“…It is early to rule out SPC as a marker, given the heterogeneity of breast cancer. SPC levels are reportedly increased in plasma of metabolic syndrome patients [21]. Furthermore, HDL and its receptor, scavenger receptor class B type I appear to affect the aggressive prognosis of breast cancer [22].…”

Section: Discussionmentioning

confidence: 99%

“…SPC induces the scratching response in mice via degranulation of mast cells and is also a proinflammatory mediator in cerebral arteries [18][19][20]. SPC levels are reportedly increased in plasma of metabolic syndrome patients [21]. Furthermore, HDL and its receptor, scavenger receptor class B type I appear to affect the aggressive prognosis of breast cancer [22].…”

Section: Introductionmentioning

confidence: 99%

Novel effects of sphingosylphosphorylcholine on invasion of breast cancer: Involvement of matrix metalloproteinase-3 secretion leading to WNT activation

Kim

Kang

Kim

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Sphingosylphosphorylcholine (SPC) participates in several cellular processes including metastasis. SPC induces keratin reorganization and regulates the viscoelasticity of metastatic cancer cells including PANC-1 cancer cells leading to enhanced migration and invasion. The role of SPC and the relevant mechanism in invasion of breast cell are as yet unknown. SPC dose-dependently induces invasion of breast cancer cells or breast immortalized cells. Reverse transcription polymerase chain reaction and Western blot analyses of MCF10A and ZR-75-1 cells indicated that SPC induces expression and secretion of matrix metalloproteinase-3 (MMP3). From online KMPLOT, relapse free survival is high in patients having low MMP3 expressed basal breast cancer (n=581, p=0.032). UK370106 (MMP3 inhibitor) or gene silencing of MMP3 markedly inhibited the SPC-induced invasion of MCF10A cells. An extracellular signal-regulated kinase (ERK) inhibitor, PD98059, significantly suppressed the secretion and the gelatinolytic activity of MMP3, and invasion in MCF10A cells. Over-expression of ERK1 and ERK2 promoted both the expression and secretion of MMP3. In contrast, gene silencing of ERK1 and ERK2 attenuated the secretion of MMP3 in MCF10A cells. The effects of SPC-induced MMP3 secretion on β-catenin and TCF/lymphoid enhancer factor (LEF) promoter activity were examined since MMP3 indirectly activates canonical Wnt signaling. SPC induced translocation of β-catenin to nucleus and increased TCF/LEF promoter activity. These events were suppressed by UK370106 or PD98059. Wnt inhibitor, FH535 inhibited SPC-induced MMP3 secretion and invasion. Taken together, these results suggest that SPC induces MMP3 expression and secretion via ERK leading to Wnt activation.

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Increased Levels of Sphingosylphosphorylcholine (SPC) in Plasma of Metabolic Syndrome Patients

Cited by 19 publications

References 56 publications

Identification of key lipids critical for platelet activation by comprehensive analysis of the platelet lipidome

Identification of key lipids critical for platelet activation by comprehensive analysis of the platelet lipidome

LC-MS/MS multiplex analysis of lysosphingolipids in plasma and amniotic fluid: A novel tool for the screening of sphingolipidoses and Niemann-Pick type C disease

Novel effects of sphingosylphosphorylcholine on invasion of breast cancer: Involvement of matrix metalloproteinase-3 secretion leading to WNT activation

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