Plasma Sphingosine-1-phosphate Research Articles

U-shaped association between plasma sphingosine-1-phosphate levels and mortality in patients with chronic systolic heart failure: a prospective cohort study

BackgroundThe endogenous lipid molecule sphingosine-1-phosphate (S1P) has received attention in the cardiovascular field due to its significant cardioprotective effects, as revealed in animal studies. The purpose of our study was to identify the distribution characteristics of S1P in systolic heart failure patients and the prognostic value of S1P for long-term prognosis.MethodsWe recruited 210 chronic systolic heart failure patients from June 2014 to December 2015. Meanwhile 54 healthy people in the same area were selected as controls. Plasma S1P was measured by liquid chromatography-tandem mass spectrometry. Patients were grouped according to the baseline S1P level quartiles, and restricted cubic spline plots described the association between S1P and all-cause death. Cox proportional hazard analysis was used to determine the relationship between category of S1P and all-cause death.ResultsCompared with the control group, the plasma S1P in chronic heart failure patients demonstrated a higher mean level (1.269 μmol/L vs 1.122 μmol/L, P = 0.006) and a larger standard deviation (0.441 vs 0.316, P = 0.022). Based on multivariable Cox regression with restricted cubic spline analysis, a non-linear and U-shaped association between S1P levels and the risk of all-cause death was observed. After a follow-up period of 31.7 ± 10.3 months, the second quartile (0.967–1.192 μml/L) with largely normal S1P levels had the lowest all-cause mortality and either an increase (adjusted HR = 2.368, 95%CI 1.006–5.572, P = 0.048) or a decrease (adjusted HR = 0.041, 95%CI 0.002–0.808, P = 0.036) predicted a worse prognosis. The survival curves showed that patients in the lowest quartile and highest quartile were at a higher risk of death.ConclusionsPlasma S1P levels in systolic heart failure patients are related to the long-term all-cause mortality with a U-shaped correlation.Trial registrationCHiCTR, ChiCTR-ONC-14004463. Registered 20 March 2014.

Therapeutic Inhibition of Sphingosine Kinase SphK2 lowers Blood Pressure Levels in an Experimental Model of Hypertension by Reducing CD4+ T‐cell Responses

Hypertension is a major cause of premature death in the world and the primary contributor to target organ damage. Although many therapeutic strategies to combat hypertension and its comorbidities exist, none of the current anti‐hypertension medications target the immune system, which evolved as key player in the pathogenesis of hypertension. During hypertension, the activation of the immune system links to alterations in sphingosine‐1‐phosphate (S1P) signaling and specifically, to sphingosine kinase 2 (SphK2)‐mediated immune cell chemotaxis. Our previous findings revealed a protection from the development of hypertension in SphK2 knockout mice. In this study, we explored the efficacy of pharmacological SphK2 inhibition to lowering elevated blood pressure and immune activation during angiotensin II‐induced hypertension in mice.In a murine model of hypertension where we treated mice with the SphK2 inhibitor ABC294640 or saline for two weeks, we assessed BP levels using tail cuff plethysmography, immune cell populations using flow cytometry, and circulating S1P levels using mass spectrometry. Using decision trees as a method of supervised machine learning, we set out to identify a sequential set of rules on measurement outcomes, which predict a successful reduction of BP.Pharmacological SphK2 inhibition significantly lowered BP levels, without affecting plasma S1P levels. Notwithstanding its incapacity to lower S1P plasma levels, pharmacological SphK2 inhibition drastically affected T‐cell populations in the blood as evidenced by significantly reduced overall circulating CD4+ T‐cells compared to placebo‐treated hypertensive mice. Besides dampening T‐cell responses typically associated to hypertension (i.e., TH17 and TH1 responses), pharmacological SphK2 inhibition resulted in marked increases of the IL4+TH2 subset. Interestingly, the rules learned by a decision tree identify CD4+ T‐cells as critical modulators for BP responses. Thus, therapeutic administration of CD4 blocking antibody diminished the number of circulating CD4+ T‐cells and significantly lowered elevated blood pressure levels.Our results provide profound evidence that the SphK2‐S1P signaling axis regulates systemic immune cell homeostasis and T‐cell phenotype changes important to blood pressure regulation. Taken together, our work identified first evidence for SphK2 inhibitors as successful immune‐based therapy in hypertension.Support or Funding InformationThis research was supported by the Swedish Research Council (VR 2017‐01243), the Ake Wibergs Stiftelse (M17‐0031), and the Knut & Alice Wallenberg Foundation.

Activation of sphingosine 1-phosphate receptor 2 attenuates chemotherapy-induced neuropathy.

Platinum-based therapeutics are used to manage many forms of cancer, but frequently result in peripheral neuropathy. Currently, the only option available to attenuate chemotherapy-induced neuropathy is to limit or discontinue this treatment. Sphingosine 1-phosphate (S1P) is a lipid-based signaling molecule involved in neuroinflammatory processes by interacting with its five cognate receptors: S1P1-5 In this study, using a combination of drug pharmacodynamic analysis in human study participants, disease modeling in rodents, and cell-based assays, we examined whether S1P signaling may represent a potential target in the treatment of chemotherapy-induced neuropathy. To this end, we first investigated the effects of platinum-based drugs on plasma S1P levels in human cancer patients. Our analysis revealed that oxaliplatin treatment specifically increases one S1P species, d16:1 S1P, in these patients. Although d16:1 S1P is an S1P2 agonist, it has lower potency than the most abundant S1P species (d18:1 S1P). Therefore, as d16:1 S1P concentration increases, it is likely to disproportionately activate proinflammatory S1P1 signaling, shifting the balance away from S1P2 We further show that a selective S1P2 agonist, CYM-5478, reduces allodynia in a rat model of cisplatin-induced neuropathy and attenuates the associated inflammatory processes in the dorsal root ganglia, likely by activating stress-response proteins, including ATF3 and HO-1. Cumulatively, the findings of our study suggest that the development of a specific S1P2 agonist may represent a promising therapeutic approach for the management of chemotherapy-induced neuropathy.

Identification of ApoA4 as a sphingosine 1-phosphate chaperone in ApoM- and albumin-deficient mice

HDL-bound ApoM and albumin are protein chaperones for the circulating bioactive lipid, sphingosine 1-phosphate (S1P); in this role, they support essential extracellular S1P signaling functions in the vascular and immune systems. We previously showed that ApoM- and albumin-bound S1P exhibit differences in receptor activation and biological functions. Whether the physiological functions of S1P require chaperones is not clear. We examined ApoM-deficient, albumin-deficient, and double-KO (DKO) mice for circulatory S1P and its biological functions. In albumin-deficient mice, ApoM was upregulated, thus enabling S1P functions in embryonic development and postnatal adult life. The Apom:Alb DKO mice reproduced, were viable, and exhibited largely normal vascular and immune functions, which suggested sufficient extracellular S1P signaling. However, Apom:Alb DKO mice had reduced levels (∼25%) of plasma S1P, suggesting that novel S1P chaperones exist to mediate S1P functions. In this study, we report the identification of ApoA4 as a novel S1P binding protein. Recombinant ApoA4 bound to S1P, activated multiple S1P receptors, and promoted vascular endothelial barrier function, all reflective of its function as a S1P chaperone in the absence of ApoM and albumin. We suggest that multiple S1P chaperones evolved to support complex and essential extracellular signaling functions of this lysolipid mediator in a redundant manner.

Plasma apoM and S1P levels are inversely associated with mortality in African Americans with type 2 diabetes mellitus

apoM is a minor HDL apolipoprotein and carrier for sphingosine-1-phosphate (S1P). HDL apoM and S1P concentrations are inversely associated with atherosclerosis progression in rodents. We evaluated associations between plasma concentrations of S1P, plasma concentrations of apoM, and HDL apoM levels with prevalent subclinical atherosclerosis and mortality in the African American-Diabetes Heart Study participants (N = 545). Associations between plasma S1P, plasma apoM, and HDL apoM with subclinical atherosclerosis and mortality were assessed using multivariate parametric, nonparametric, and Cox proportional hazards models. At baseline, participants' median (25th percentile, 75th percentile) age was 55 (49, 62) years old and their coronary artery calcium (CAC) mass score was 26.5 (0.0, 346.5). Plasma S1P, plasma apoM, and HDL apoM were not associated with CAC. After 64 (57.6, 70.3) months of follow-up, 81 deaths were recorded. Higher concentrations of plasma S1P [odds ratio (OR) = 0.14, P = 0.01] and plasma apoM (OR = 0.10, P = 0.02), but not HDL apoM (P = 0.89), were associated with lower mortality after adjusting for age, sex, statin use, CAC, kidney function, and albuminuria. We conclude that plasma S1P and apoM concentrations are inversely and independently associated with mortality, but not CAC, in African Americans with type 2 diabetes after accounting for conventional risk factors.

Circulating sphingosine-1-phosphate as a prognostic biomarker for community-acquired pneumonia.

Early determination of the severity of Community-Acquired Pneumonia (CAP) is essential for better disease prognosis. Current predictors are suboptimal, and their clinical utility remains to be defined, highlighting the need for developing biomarkers with efficacious prognostic value. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid with a documented regulatory role in immune defense and maintenance of endothelial barrier integrity. For early diagnose of CAP and recognition of severe CAP patients, we conduct this pilot study to access the potential utility of the circulating S1P in an Emergency department setting. In the prospective study, plasma S1P levels were quantified in healthy controls and patients with CAP. Also, their discriminating power was assessed by receiver operating characteristic analysis. The association between S1P levels and disease severity indices was assessed by Spearman correlation and logistic regression tests. Patients with CAP had significantly higher plasma S1P levels than healthy individuals (CAP: 27.54 ng/ml, IQR = 14.37–49.99 ng/ml; Controls: 10.58 ng/ml, IQR = 4.781–18.91 ng/ml; p < 0.0001). S1P levels were inversely correlated with disease severity in patients with CAP. Based on multivariate logistic regression analysis, the plasma S1P concentrations showed significant predicting power for mortality (OR: 0.909; CI: 0.801–0.985; p < 0.05), intensive care unit admission (OR: 0.89; CI: 0.812–0.953; p < 0.005) and long hospital stay (OR: 0.978; CI: 0.961–0.992; p < 0.005). Interestingly, significantly elevated levels of S1P were noted in patients who received methylprednisolone treatment during hospitalization. These results suggest that S1P may be associated with the pathogenesis of CAP and may have prognostic utility in CAP and its therapy, especially in the Emergency Department setting.

Loss of sphingosine 1-phosphate (S1P) in septic shock is predominantly caused by decreased levels of high-density lipoproteins (HDL)

BackgroundSphingosine 1-phosphate (S1P) is a signaling lipid essential in regulating processes involved in sepsis pathophysiology, including endothelial permeability and vascular tone. Serum S1P is progressively reduced in sepsis patients with increasing severity. S1P function depends on binding to its carriers: serum albumin (SA) and high-density lipoproteins (HDL). The aim of this single-center prospective observational study was to determine the contribution of SA- and HDL-associated S1P (SA-S1P and HDL-S1P) to sepsis-induced S1P depletion in plasma with regard to identify future strategies to supplement vasoprotective S1P.MethodsSequential precipitation of lipoproteins was performed with plasma samples obtained from 100 ICU patients: surgical trauma (n = 20), sepsis (n = 63), and septic shock (n = 17) together with healthy controls (n = 7). Resultant fractions with HDL and SA were analyzed by liquid chromatography coupled to triple-quadrupole mass spectrometry (LC-MS/MS) for their S1P content.ResultsPlasma S1P levels significantly decreased with sepsis severity and showed a strong negative correlation with increased organ failure, quantified by the Sequential Organ Failure Assessment (SOFA) score (rho − 0.59, P < 0.001). In controls, total plasma S1P levels were 208 μg/L (187–216 μg/L). In trauma patients, we observed an early loss of SA-S1P (− 70%) with a concurrent increase of HDL-S1P (+ 20%), resulting in unaltered total plasma S1P with 210 μg/L (143–257 μg/L). The decrease of plasma S1P levels with increasing SOFA score in sepsis patients with 180.2 μg/L (123.3–253.0 μg/L) and in septic shock patients with 99.5 μg/L (80.2–127.2 μg/L) was mainly dependent on equivalent reductions of HDL and not SA as carrier protein. Thus, HDL-S1P contributed most to total plasma S1P in patients and progressively dropped with increasing SOFA score.ConclusionsReduced plasma S1P was associated with sepsis-induced organ failure. A constant plasma S1P level during the acute phase after surgery was maintained with increased HDL-S1P and decreased SA-S1P, suggesting the redistribution of plasma S1P from SA to HDL. The decrease of plasma S1P levels in patients with increasing sepsis severity was mainly caused by decreasing HDL and HDL-S1P. Therefore, strategies to reconstitute HDL-S1P rather than SA-S1P should be considered for sepsis patients.

UHPLC-MS/MS analysis of sphingosine 1-phosphate in joint cavity dialysate and hemodialysis solution of adjuvant arthritis rats: Application to geniposide pharmacodynamic study.

Geniposide (GE) is an iridoid glycoside compound with anti-inflammatory effect. The potential of sphingosine 1-phosphate (S1P) as a plasma marker in human diseases was suggested recently in the literature, which demonstrated that, in patients with inflammatory diseases, plasma S1P was elevated. It follows that the obstructive coronary artery disease can be predicted with serum S1P. Therefore, S1P can also be potentially used as a pharmacodynamic marker to study adjuvant arthritis (AA) rats. In the current study, a UHPLC-MS/MS method combined with the microdialysis sampling technique (using FTY720 phosphate as an internal standard) was adopted and validated to measure S1P levels in the hemodialysis fluid and joint cavity dialysates of AA rats after oral administration of GE. A S1P concentration-time curve in the dialysate was established in this study. It was demonstrated that GE exerted an anti-inflammatory effect by reducing AA-induced elevated S1P levels. It is showed that changes in S1P concentrations over time can be used to monitor the pharmacodynamic effects of GE in treating AA rats in pharmacodynamic studies.

Differential expression of S1P receptor subtypes in human bladder transitional cell carcinoma.

Sphingosine 1 phosphate (S1P), S1P receptors (S1PRs) and their signaling pathways play an important role in the fate of cancer cells. The expression pattern of S1PR subtypes (S1PR1-S1PR5) may alter in cancer development stages, depending on the origin and the pathologic features of tumors. The present study aimed to examine the relationship between plasma S1P levels and the expression of S1PR subtypes in bladder tumors. These changes were evaluated in terms of the pathologic grades and stages of human bladder cancer samples. For this, tumor biopsies from 41 new bladder cancer patients as well as 26 normal-looking bladder tissues were collected and processed for immunohistochemistry (IHC) and quantitative real-time RT-PCR of S1PR subtypes. Plasma S1P level was measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The results show that tissue S1PR1, S1PR2 and S1PR3 are over-expressed in all tumors regardless of their pathological grade (~ 3, ~ 6 and ~ 104 folds, respectively). These results were corroborated by IHC data showing accumulation of S1PR subtypes 1 and 2 in the tissues. Plasma S1P in the plasma samples from patients was in the range of control samples (Controls; 256 ± 47; patients, 270 ± 41). Overexpression of S1PR1, S1PR2 and S1PR3 in bladder tumor biopsies which were corroborated with the pathological grades and stages may suggest that S1PR profile in tumor biopsies is a promising marker in the diagnosis of bladder carcinoma.

Altered Sphingolipid Metabolism Is Associated With Asthma Phenotype in House Dust Mite-Allergic Patients.

PurposeSphingolipids play an important role in cell growth, survival, inflammation and tissue remodeling. House dust mite (HDM) allergy is a major risk factor for asthma. The aim of the study was to evaluate if allergic asthma phenotype is associated with altered sphingolipid metabolism.MethodsTwenty-two HDM-allergic asthmatic patients and 11 HDM-allergic rhinitis patients were challenged intrabronchially with biologically standardized Dermatophagoides pteronyssinus extract. Whole blood and platelet-poor plasma samples were collected before, during early asthmatic response (EAR), late asthmatic response (LAR) and 24 hours after the challenge. Concentrations of sphinganine (SFA), sphinganine-1-phosphate (SFA1P), ceramide, sphingosine (SFO) and sphingosine-1-phosphate (S1P) were measured using high performance liquid chromatography.ResultsIn all house dust mite-allergic patients (HDM-APs), baseline lung function and severity of airway hyperreactivity (AHR) correlated significantly with plasma S1P and SFA1P concentrations. Exhaled nitric oxide concentration, however, correlated with SFA and ceramide, but not with S1P or SFA1P concentration. Allergen challenge increased plasma S1P concentration during EAR, but only in patients who developed both EAR and LAR. The magnitude of the increase determined during EAR correlated with the severity of subsequently developed LAR. Platelet and eosinophil counts were independent predictors of plasma S1P concentration. A significant increase in plasma SFA concentration in response to allergen challenge was seen only in patients who did not develop asthmatic response.ConclusionsAltered sphingolipid metabolism, with augmented synthesis of S1P and impaired de novo sphingolipid synthesis in response to allergen challenge, may participate in the development of asthma phenotype in HDM-APs.

Association between Sphingosine-1-Phosphate and Bone Characteristics in Men and Post-menopausal Women in Malaysia

Event Abstract Back to Event Association between Sphingosine-1-Phosphate and Bone Characteristics in Men and Post-menopausal Women in Malaysia Nasrin Shahifar1, Subashini C. Thambiah1, Siti Yazmin Zahari Sham1, Salmiah Md Said2, Swan S. Yeap3, 4, Fen L. Hew3, 4 and Intan Nureslyna Samsudin1* 1 Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Malaysia 2 Department of Community Health, Faculty of Medicine and Health Sciences, Putra Malaysia University, Malaysia 3 Puchong Specialist Clinic, Malaysia 4 Subang Jaya Medical Centre, Malaysia Background Prevention of osteoporotic fracture requires identification of individuals at high risk of fracture. There remains an inadequate predictive discrimination ability of current tools to identify those at risk. Sphingosine-1-phosphate (S1P) being a novel marker of bone metabolism may complement the current model. We determined the association between plasma S1P with sociodemographic factors, clinical characteristics, bone mineral density (BMD) and blood tests for bone profile among healthy adult residents of Puchong and Kajang, Malaysia. Methods A cross-sectional study was carried out involving Chinese subjects aged 50-90 years old with no previous history of osteoporosis who attended a health screening program in Puchong Specialist Clinic. Each subject had a BMD determined by a dual-energy x-ray absorptiometry (DXA) scan. Fasting blood samples were analysed for 25-hydroxyvitamin D, parathyroid hormone (iPTH), calcium, phosphate, procollagen type 1 amino-terminal propeptide (P1NP), carboxy-terminal collagen crosslinks (CTX) and S1P. Pearson’s and Spearman’s correlation tests were used to determine the associations between S1P with sociodemographic factors and bone characteristic parameters. Results There were 45 (34.4%) males and 86 (65.6%) post-menopausal women with median age of 65 (IQR=17) years old. Osteopaenia and osteoporosis were noted in 46.6% and 29.0% of study subjects, respectively. The S1P levels in men (2.12±0.75 µmol/L) and post-menopausal women (1.96±0.68 µmol/L) were not statistically different (p=0.235). S1P had a moderate negative correlation with iPTH (r=-0.232; p=0.008) but not with the other laboratory parameters, age, body mass index and individual BMD values at various sites in both men and post-menopausal women. Conclusion Osteoporosis was diagnosed in almost 30% of subjects. S1P levels did not differ between genders. It did not correlate with either of the bone turnover markers (P1NP and CTX) nor with any BMD values at various sites. S1P levels in the subjects were however low which may suggest that the risk of future osteoporotic fracture is low. Keywords: Sphingosine-1-phosphate, Osteoporosis, osteopenia, Men, post-menopausal women Conference: International Conference on Drug Discovery and Translational Medicine 2018 (ICDDTM '18) “Seizing Opportunities and Addressing Challenges of Precision Medicine”, Putrajaya, Malaysia, 3 Dec - 5 Feb, 2019. Presentation Type: Poster Presentation Topic: Miscellaneous Citation: Shahifar N, Thambiah SC, Zahari Sham S, Md Said S, Yeap SS, Hew FL and Samsudin I (2019). Association between Sphingosine-1-Phosphate and Bone Characteristics in Men and Post-menopausal Women in Malaysia. Front. Pharmacol. Conference Abstract: International Conference on Drug Discovery and Translational Medicine 2018 (ICDDTM '18) “Seizing Opportunities and Addressing Challenges of Precision Medicine”. doi: 10.3389/conf.fphar.2019.63.00026 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 08 Nov 2018; Published Online: 17 Jan 2019. * Correspondence: Dr. Intan Nureslyna Samsudin, Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor Daruh Ehsan, Selangor, 43400, Malaysia, intanlyna@upm.edu.my Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Nasrin Shahifar Subashini C Thambiah Siti Yazmin Zahari Sham Salmiah Md Said Swan S Yeap Fen L Hew Intan Nureslyna Samsudin Google Nasrin Shahifar Subashini C Thambiah Siti Yazmin Zahari Sham Salmiah Md Said Swan S Yeap Fen L Hew Intan Nureslyna Samsudin Google Scholar Nasrin Shahifar Subashini C Thambiah Siti Yazmin Zahari Sham Salmiah Md Said Swan S Yeap Fen L Hew Intan Nureslyna Samsudin PubMed Nasrin Shahifar Subashini C Thambiah Siti Yazmin Zahari Sham Salmiah Md Said Swan S Yeap Fen L Hew Intan Nureslyna Samsudin Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Correction: Mobilization studies in mice deficient in sphingosine kinase 2 support a crucial role of the plasma level of sphingosine-1-phosphate in the egress of hematopoietic stem progenitor cells.

[This corrects the article DOI: 10.18632/oncotarget.19514.].

Visceral fat accumulation is associated with increased plasma sphingosine-1-phosphate levels in type 2 diabetes mellitus

ObjectiveAccumulating evidence has shown that sphingosine-1-phosphate (S1P) plays roles in glucose and fat metabolism. However, the association between plasma S1P levels and fat mass, especially visceral fat mass, remains unknown. MethodsIn this cross-sectional study, 80 men with type 2 diabetes mellitus (T2DM) were recruited to investigate the association of plasma S1P levels with body fat parameters. Visceral (VFA) and subcutaneous fat (SFA) areas were evaluated by performing computed tomography scan, and fat mass (FM) and lean body mass (LBM) were examined by whole body dual-energy X-ray absorptiometry. ResultsMultiple regression analysis adjusted for age, T2DM duration, serum creatinine, and body mass index (BMI) showed that S1P was significantly and positively associated with fasting plasma glucose (β = 0.25, p = 0.027), HbA1c (β = 0.28, p = 0.012), and urine C-peptide (β = 0.29, p = 0.014). Moreover, multiple regression analysis adjusted for age, T2DM duration, serum creatinine, HbA1c, and urine C-peptide showed that BMI (β = 0.32, p = 0.008), VFA (β = 0.33, p = 0.008), SFA (β = 0.26, p = 0.039), FM (β = 0.37, p = 0.003), and LBM (β = 0.35, p = 0.01). FM was significantly and positively associated with S1P after additional adjustment for LBM (β = 0.29, p = 0.028), whereas LBM was not after adjustment for FM. Moreover, VFA was significantly and positively associated with S1P after additional adjustment for SFA (β = 0.27, p = 0.039), whereas SFA was not after adjustment for VFA. ConclusionThis is the first study to show that increased plasma S1P levels are associated with blood glucose levels and accumulation of fat mass, especially visceral fat mass, in men with T2DM.

Regulation of the metabolism of apolipoprotein M and sphingosine 1-phosphate by hepatic PPARγ activity.

Apolipoprotein M (apoM) is a carrier and a modulator of sphingosine 1-phosphate (S1P), an important multifunctional bioactive lipid. Since peroxisome proliferator-activated receptor γ (PPARγ) is reportedly associated with the function and metabolism of S1P, we investigated the modulation of apoM/S1P homeostasis by PPARγ. First, we investigated the modulation of apoM and S1P homeostasis by the overexpression or knockdown of PPARγ in HepG2 cells and found that both the overexpression and the knockdown of PPARγ decreased apoM expression and S1P synthesis. When we activated or suppressed the PPARγ more mildly with pioglitazone or GW9662, we found that pioglitazone suppressed apoM expression and S1P synthesis, while GW9662 increased them. Next, we overexpressed PPARγ in mouse liver through adenoviral gene transfer and observed that both the plasma and hepatic apoM levels and the plasma S1P levels decreased, while the hepatic S1P levels increased, in the presence of enhanced sphingosine kinase activity. Treatment with pioglitazone decreased both the plasma and hepatic apoM and S1P levels only in diet-induced obese mice. Moreover, the overexpression of apoM increased, while the knockdown of apoM suppressed PPARγ activities in HepG2 cells. These results suggested that PPARγ regulates the S1P levels by modulating apoM in a bell-shaped manner, with the greatest levels of apoM/S1P observed when PPARγ was mildly expressed and that hepatic apoM/PPARγ axis might maintain the homeostasis of S1P metabolism.

Aryl hydrocarbon receptor signaling promotes ORMDL3-dependent generation of sphingosine-1-phosphate by inhibiting sphingosine-1-phosphate lyase.

Aryl hydrocarbon receptor (AhR), a cellular chemical sensor, controls cellular homeostasis, and sphingosine-1-phosphate (S1P), a bioactive intermediate of sphingolipid metabolism, is believed to have a role in immunity and inflammation, but their potential crosstalk is currently unknown. We aimed to determine whether there is a functional linkage between AhR signaling and sphingolipid metabolism. We showed that AhR ligands, including an environmental polycyclic aromatic hydrocarbon (PAH), induced S1P generation, and inhibited S1P lyase (S1PL) activity in resting cells, antigen/IgE-activated mast cells, and mouse lungs exposed to the AhR ligand alone or in combination with antigen challenge. The reduction of S1PL activity was due to AhR-mediated oxidation of S1PL at residue 317, which was reversible by the addition of an antioxidant or in cells with knockdown of the ORMDL3 gene encoding an ER transmembrane protein, whereas C317A S1PL mutant-transfected cells were resistant to the AhR-mediated effect. Furthermore, analysis of AhR ligand-treated cells showed a time-dependent increase of the ORMDL3-S1PL complex, which was confirmed by FRET analysis. This change increased the S1P levels, which in turn, induced mast cell degranulation via S1PR2 signaling. In addition, elevated levels of plasma S1P were found in children with asthma compared to non-asthmatic subjects. These results suggest a new regulatory pathway whereby the AhR-ligand axis induces ORMDL3-dependent S1P generation by inhibiting S1PL, which may contribute to the expression of allergic diseases.

Divergent Role of Sphingosine 1-Phosphate in Liver Health and Disease.

Two decades ago, sphingosine 1-phosphate (S1P) was discovered as a novel bioactive molecule that regulates a variety of cellular functions. The plethora of S1P-mediated effects is due to the fact that the sphingolipid not only modulates intracellular functions but also acts as a ligand of G protein-coupled receptors after secretion into the extracellular environment. In the plasma, S1P is found in high concentrations, modulating immune cell trafficking and vascular endothelial integrity. The liver is engaged in modulating the plasma S1P content, as it produces apolipoprotein M, which is a chaperone for the S1P transport. Moreover, the liver plays a substantial role in glucose and lipid homeostasis. A dysfunction of glucose and lipid metabolism is connected with the development of liver diseases such as hepatic insulin resistance, non-alcoholic fatty liver disease, or liver fibrosis. Recent studies indicate that S1P is involved in liver pathophysiology and contributes to the development of liver diseases. In this review, the current state of knowledge about S1P and its signaling in the liver is summarized with a specific focus on the dysregulation of S1P signaling in obesity-mediated liver diseases. Thus, the modulation of S1P signaling can be considered as a potential therapeutic target for the treatment of hepatic diseases.

Alkaline ceramidase 2 is essential for the homeostasis of plasma sphingoid bases and their phosphates.

Sphingosine-1-phosphate (S1P) plays important roles in cardiovascular development and immunity. S1P is abundant in plasma because erythrocytes-the major source of S1P-lack any S1P-degrading activity; however, much remains unclear about the source of the plasma S1P precursor, sphingosine (SPH), derived mainly from the hydrolysis of ceramides by the action of ceramidases that are encoded by 5 distinct genes, acid ceramidase 1 ( ASAH1)/ Asah1, ASAH2/ Asah2, alkaline ceramidase 1 ( ACER1)/ Acer1, ACER2/ Acer2, and ACER3/ Acer3, in humans/mice. Previous studies have reported that knocking out Asah1 or Asah2 failed to reduce plasma SPH and S1P levels in mice. In this study, we show that knocking out Acer1 or Acer3 also failed to reduce the blood levels of SPH or S1P in mice. In contrast, knocking out Acer2 from either whole-body or the hematopoietic lineage markedly decreased the blood levels of SPH and S1P in mice. Of interest, knocking out Acer2 from whole-body or the hematopoietic lineage also markedly decreased the levels of dihydrosphingosine (dhSPH) and dihydrosphingosine-1-phosphate (dhS1P) in blood. Taken together, these results suggest that ACER2 plays a key role in the maintenance of high plasma levels of sphingoid base-1-phosphates-S1P and dhS1P-by controlling the generation of sphingoid bases-SPH and dhSPH-in hematopoietic cells.-Li, F., Xu, R., Low, B. E., Lin, C.-L., Garcia-Barros, M., Schrandt, J., Mileva, I., Snider, A., Luo, C. K., Jiang, X.-C., Li, M.-S., Hannun, Y. A., Obeid, L. M., Wiles, M. V., Mao, C. Alkaline ceramidase 2 is essential for the homeostasis of plasma sphingoid bases and their phosphates.

High Plasma Sphingosine 1-phosphate Levels Predict Osteoporotic Fractures in Postmenopausal Women: The Center of Excellence for Osteoporosis Research Study.

BackgroundHigher sphingosine 1-phosphate (S1P) plasma levels are associated with decreased bone mineral density (BMD), and increased risk of prevalent vertebral fracture. So, we hypothesized that postmenopausal women with increased baseline plasma S1P levels have a greater risk for future incident fracture (osteoporosis-related fractures [ORFs]).MethodsThis study was conducted in a prospective longitudinal cohort of 707 women recruited in 2004 and followed up annually for a mean period of 5.2±1.3 years. They were postmenopausal (aged ≥50 years). The primary outcome measure was the time to the first confirmed ORF event using radiographs and/or a surgical report.ResultsThe plasma S1P levels (µmol/L) were significantly higher in the women with incident fracture (7.23±0.79) than in those without ORFs (5.02±0.51; P<0.001). High S1P levels were strongly associated with increased fracture risk. After adjustment for age and other confounders, the hazard ratio (HR) was 6.12 (95% confidence interval [CI], 4.92−7.66) for each 1-standard deviation increase in plasma S1P levels. The women in the highest quartile of S1P levels had a significant increase in fracture risk (HR, 9.89; 95% CI, 2.83−34.44). Results were similar when we compared plasma S1P levels at the 1-year visit.ConclusionsThe associations between plasma S1P levels and fracture risk were independent of BMD and other confounders. These findings demonstrate that high plasma S1P level at baseline and at years 1 to 5 is a strong and independent risk factor for future [ORFs] among postmenopausal women and could be a useful biomarker for fracture risk assessment in this population.

Sphingosine 1-Phosphate and Atherosclerosis.

Sphingosine 1-phosphate (S1P) is a potent lipid mediator that works on five kinds of S1P receptors located on the cell membrane. In the circulation, S1P is distributed to HDL, followed by albumin. Since S1P and HDL share several bioactivities, S1P is believed to be responsible for the pleiotropic effects of HDL. Plasma S1P levels are reportedly lower in subjects with coronary artery disease, suggesting that S1P might be deeply involved in the pathogenesis of atherosclerosis. In basic experiments, however, S1P appears to possess both pro-atherosclerotic and anti-atherosclerotic properties; for example, S1P possesses anti-apoptosis, anti-inflammation, and vaso-relaxation properties and maintains the barrier function of endothelial cells, while S1P also promotes the egress and activation of lymphocytes and exhibits pro-thrombotic properties. Recently, the mechanism for the biased distribution of S1P on HDL has been elucidated; apolipoprotein M (apoM) carries S1P on HDL. ApoM is also a modulator of S1P, and the metabolism of apoM-containing lipoproteins largely affects the plasma S1P level. Moreover, apoM modulates the biological properties of S1P. S1P bound to albumin exerts both beneficial and harmful effects in the pathogenesis of atherosclerosis, while S1P bound to apoM strengthens anti-atherosclerotic properties and might weaken the pro-atherosclerotic properties of S1P. Although the detailed mechanisms remain to be elucidated, apoM and S1P might be novel targets for the alleviation of atherosclerotic diseases in the future.

Arteriovenous Sphingosine-1-Phosphate Differences Across Selected Organs of the Rat

Background/Aims: Sphingosine-1-phosphate (S1P) is a bioactive lysosphingolipid that is found in high concentration in plasma. The majority of plasma S1P is transported bound to HDL and albumin. Although the major sources of circulating S1P have been identified, it remains obscure what is the contribution of different organs/tissues to S1P homeostasis in plasma. Answering this question was the major aim of the present study. Methods: The experiment was performed on male Wistar rats from whom blood samples were taken from either: 1) femoral vein, right ventricle of the heart, and abdominal aorta (n=15) or 2) hepatic vein, portal vein, and abdominal aorta (n=11). Plasma was fractionated by sequential flotation ultracentrifugation and sphingolipids were quantified by a HPLC method. Results: Compared to the mixed venous blood sampled from the right ventricle, total plasma and lipoprotein-depleted plasma (LPDP) concentration of S1P in the arterial blood was lower. On the other hand, the level of S1P increased across the leg both in plasma and LPDP. The concentration of S1P, sphingosine, and sphinganine in the plasma, HDL, and LPDP isolated from the blood taken from the hepatic vein was markedly higher compared to both arterial and portal blood. Conclusions: We conclude that, in contrast to HDL-bound S1P, albumin-associated S1P is very labile in the circulation. It is degraded in the pulmonary, and to a lesser extent, gastrointestinal circulation, and released across the liver and skeletal muscle. We also conclude that liver is an important source of HDL-bound S1P and circulating free sphingoid bases.