High Levels Of Ceramide Research Articles

Ion Mobility QTOF-MS Untargeted Lipidomics of Human Serum Reveals a Metabolic Fingerprint for GNE Myopathy

GNE myopathy, also known as hereditary inclusion body myopathy (HIBM), is a rare genetic muscle disorder marked by a gradual onset of muscle weakness in young adults. GNE myopathy (GNEM) is caused by bi-allelic variants in the UDP-N-acetylglucosamine 2-epimerase (UDP-GlcNAc 2-epimerase)/N-acetylmannosamine kinase (ManNAc kinase) gene (GNE), clinically resulting in the loss of ambulation within 10–20 years from the onset of the initial symptoms. The disease’s mechanism is poorly understood and non-invasive biomarkers are lacking, hindering effective therapy development. Based on the available evidence, we employed a lipidomic approach to study the serum lipid profile of GNE patients. The multivariate statistical analysis revealed a downregulation of carnitines, as well as of lysophosphatidylcholines, in sera samples derived from GNEM patients. Furthermore, we identified lower levels of sphingomyelins and, concomitantly, high levels of ceramides in serum samples from GNEM patients when compared to control samples derived from healthy donors. Moreover, the GNEM serum samples showed the upregulation of Krebs cycle intermediates, in addition to a decrease in oxaloacetic acid. The correlated data gathered in this study can offer a promising diagnostic panel of complex lipids and polar metabolites that can be used in clinic for GNEM in terms of a metabolic fingerprint measurable in a minimally invasive manner.

Ceramide As A Potential Tumor Marker For Diagnosis Of Prostate Cancer And Its Association With Lipid Profile

Background: Prostate cancer (PCa) is the second most frequent type of malignancy cancer among men worldwide. Ceramides are fatty acid derivatives of sphingoid bases, and formed not only through the de novo biosynthetic pathway, but also from the degradation of glycosphingolipids (GSLs) and ceramide-1-phosphate. Dyslipidaemia is part of metabolic syndrome, characterized by an alteration of the plasma lipid profile, including Cholesterol, HDL, and triglyceride levels. Objective Evaluate serum ceramide as tumer marker of prostate cancer and its association with lipid profile. Method This case- control study was carried out at Department of Biochemistry, College of Medicine, University of Baghdad and at Urology department, Ghazi Al-Hariri Hospital for surgical speciality during the period from March 2022 to May 2023. It included 120 men patients, 60 men patients who newly diagnosed to have primary prostate cancer (PCa), and 60 men were apparently healthy men. Investigations included serum measurements of ceramide by using enzyme linked immunosorbent assay(ELISA) and also measurement of lipid profile by using semi-auto biochemistry analyzer.Results The results of the present study showed that there was a significant differences in ceramide in prostate cancer patients as compared with the control group The results also showed that the S.Cholesterol, and S.Triglyceride were higher in the patients group compared to the controls group with significant statistical difference. Conclusion. According to the results obtained we can suggest that higher levels of ceramide, Cholesterol and Triglyceride may be associated with risk of prostate cancer.

The relationship between sphingomyelin and ceramide levels and soft neurological signs in ADHD.

Attention deficit hyperactivity disorder (ADHD), characterized by attention deficit, hyperactivity, and impulsivity, has recently been associated with lipid metabolism. In particular, the roles of sphingomyelin, ceramide, andgalactosylceramidase in the pathophysiology of ADHD are being investigated. This study aims to explore the relationship between sphingolipid metabolism markers and soft neurological signs (SNS) in children diagnosed with ADHD who are not undergoing medication treatment. A cross-sectional analysis was conducted on 41 children and adolescents aged 7-12 years diagnosed with ADHD and 39 neurotypically developing controls. Plasma levels of ceramide, sphingomyelin, and galactosylceramidase were measuredusing Enzyme-Linked Immunosorbent Assay (ELISA). SNS were assessed using the Physical and Neurological Examination for Soft Signs (PANESS). Statistical analyses included Student's t-tests, Mann-Whitney U tests, and Multivariate Analysis ofCovariance (MANCOVA), along with logistic regression analysis. Plasma levels of ceramide and sphingomyelin in children with ADHD showed significant differences compared to the neurotypically developing control group; however, there were no significant differences in galactosylceramidase levels between the two groups. Positive correlations were found between plasma levels of ceramide and sphingomyelin and the PANESS subscales F1 (Total Gait and Station) and F3 (Total Dysrhythmia). Additionally, logistic regression analysis indicated that high ceramide levels were positively associated with ADHD. This study underscores a significant association between alterations in sphingolipid metabolism (specifically increased levels of ceramide and sphingomyelin) and the presence of SNS in children with ADHD. These findings elucidate the potential role of sphingolipid metabolism in the pathophysiology of ADHD and provide suggestions for future therapeutic research targeting sphingolipid metabolism in the treatment of ADHD.

Multi-omics analysis to evaluate the effects of solar exposure and a broad-spectrum SPF50+ sunscreen on markers of skin barrier function in a skin ecosystem model.

Sun exposure induces major skin alterations, but its effects on skin metabolites and lipids remain largely unknown. Using an original reconstructed human epidermis (RHE) model colonized with human microbiota and supplemented with human sebum, we previously showed that a single dose of simulated solar radiation (SSR) significantly impacted the skin metabolome and microbiota. In this article, we further analyzed SSR-induced changes on skin metabolites and lipids in the same RHE model. Among the significantly altered metabolites (log2-fold changes with p ≤ 0.05), we found several natural moisturizing factors (NMFs): amino acids, lactate, glycerol, urocanic acid, pyrrolidone carboxylic acid and derivatives. Analyses of the stratum corneum lipids also showed that SSR induced lower levels of free fatty acids and higher levels of ceramides, cholesterols and its derivatives. An imbalance in NMFs and ceramides combined to an increase of proinflammatory lipids may participate in skin permeability barrier impairment, dehydration and inflammatory reaction to the sun. Our skin model also allowed the evaluation of an innovative ultraviolet/blue light (UV/BL) broad-spectrum sunscreen with a high sun protection factor (SPF50+). We found that using this sunscreen prior to SSR exposure could in part prevent SSR-induced alterations in NMFs and lipids in the skin ecosystem RHE model.

Ceramides from sea red rice bran ameliorate oxidative stress and lifespan in Caenorhabditis elegans by activating the p38/MAPK signaling pathway and regulating the gut microbiota

Sea red rice bran, a new salinity-tolerant sea rice by-product, contains high levels of ceramides (Cers), which are necessary to tap into their bioactivity for improving the health effects of the organism. This study aimed to investigate the effect of Cers on the improving the oxidative stress and lifespan of C. elegans, and the relationship of the interaction through the p38/MAPK signaling pathway and under the regulation of intestinal flora. The results showed that Cers treatment effectively reversed the oxidative damage caused by paraquat and hydrogen peroxide in C. elegans and reduced overexpression of ROS and accumulation of mitochondrial membrane damage. In addition, Cers intake successfully activated all gene targets of p38/MAPK signaling pathway, significantly promoted the migration of SKN-1 to the nucleus, and increased the abundance of probiotic bacteria such as Ruminoccus, AKKermansia, and Lactobacillus in the intestinal flora and effectively mitigated the adverse effects of oxidative stress. Therefore, these results indicate that Cers could be effectively in ameliorating the level of oxidative stress in the body, thereby increasing longevity and health indicators. Providing a theoretical basis for the prevention of aging-related chronic diseases and health care, and enhancing the high-value comprehensive utilization of sea red rice by-products.

Sexual dimorphism in the gonad lipidome of blue mussels (Mytilus sp.): New insights from a global lipidomics approach

Blue mussels (Mytilus sp.) are an economically important species for European aquaculture. Their importance as a food source is expected to increase in the coming net-zero society due to their low environmental footprint; however, their production is affected by anthropogenic stressors and climate change. During reproduction, lipids are key molecules for mussels as they are the main source of energy on which newly hatched embryos depend in the first days of their development. In this work, blue mussels of different origins are analysed, focusing on the differences in lipid composition between the ovary (BMO) and the testis (BMT). The lipidome of blue mussel gonads (BMG) is studied here by combining traditional lipid profiling methods, such as fatty acid and lipid class analysis, with untargeted liquid chromatography-mass spectrometry (LC-MS) lipidomics. The approach used here enabled the identification of 770 lipid molecules from 23 different lipid classes in BMG. BMT, which consists of billions of spermatocytes, had greater amounts of cell membrane and membrane lipid components such as FA18:0, C20 polyunsaturated fatty acids (PUFA), free sterols (ST), ceramide phosphoethanolamines (CerPE), ceramide aminoethylphosphonates (CAEP), cardiolipins (CL), glycerophosphocholines (PC), glycerophosphoethanolamines (PE) and glycerophosphoserines (PS). In BMO, saturated fatty acids (FA14:0 and FA16:0), monounsaturated fatty acids (MUFA) and other storage components such as C18-PUFA accumulated in triradylglycerolipids (TG) and alkyldiacylglycerols (neutral plasmalogens, TG O-), which, together with terpenes, wax esters and cholesterol esters, make up most of oocytes yolk reserves. BMO also had higher levels of ceramides (Cer) and generally alkyl/alkenyl glycerophospholipids (mainly plasmanyl/plasmenyl PC), suggesting a role for these lipids in vitellogenesis. Non-methylene interrupted dienoic fatty acids (NMID FA), typically found in plasmalogens, were the only membrane-forming PUFA predominantly detected in BMO. The results of this study are of great importance for clarifying the lipid composition of BMG and provide an important basis for future studies on the reproductive physiology of these organisms.

Contribution of ceramides metabolism in psychiatric disorders.

Psychiatric disorders affect 970 million people worldwide, representing a significant source of disability. Although the underlying neurobiological traits for these disorders are not fully understood, a complex interplay between psychological, environmental, and biological factors contributes to their outcomes. Recent advances in lipidomic analysis and artificial intelligence algorithms have improved the identification of selective lipid species modulating the susceptibility to mental disorders. Sphingolipids (SLs) and ceramides-related SLs are among the most abundant lipids species in the brain that support major key pathways during neurodevelopment and brain plasticity. High levels of ceramides in plasma and brain contribute to psychiatric illness susceptibility in humans and animal models. However, the neuropathological mechanism regarding the involvement of ceramides in these disorders remain inconclusive. The brain is highly susceptible to nutritional insults, which could lead to functional impairment and influence the development and progression of psychiatric disorders. While the brain relies on glucose metabolism to support its physiological needs, a selective nutrient formula appears to have greater effects on brain health than others. For instance, consumption of high-energy diets is associated with brain anatomical, physiological, and metabolic changes, including ceramides metabolism. Herein, we will address the contribution of ceramides metabolism as a modulator of major psychiatric disorders such as depression, anxiety, bipolar disorder, schizophrenia, and attention deficit-hyperactivity disorder. We will also describe molecular and cellular targets of ceramides metabolism assisting the maintenance and progression of psychiatric disorders and their modulation by dietary formulas as non-pharmacologic treatments.

BXQ-350: Modulating ceramide and sphingosine-1-phosphate for antitumor activity in patients with advanced CRC.

154 Background: Sphingolipids are a class of bioactive signaling molecules implicated in multiple cellular processes and molecular pathways. Many publications have demonstrated that ceramides are proapoptotic, synergize with cancer treatments, and mitigate chemoresistance. Findings also demonstrated that sphingosine-1-phosphate (S1P) is a key sphingolipid that promotes cancer cell proliferation, activates multiple oncogenic pathways, and stimulates immuno-suppressor cell populations promoting a pro-tumoral microenvironment. Several studies of colorectal cancer patients have shown high levels of ceramides being associated with improved survival, while high S1P levels are associated with a poor prognosis. Hence, modulation of sphingolipid metabolism continues to be a promising treatment approach. Methods: BXQ-350 is a nanovesicle of Saposin C, an allosteric activator of sphingolipid metabolism, that lowers systemic S1P and increases C18 ceramide. BXQ-350 was investigated in a Phase 1 dose-escalation safety study in an all-comer cancer patients with advanced solid malignancies ( NCT02859857 ) to determine its safety profile and potential clinical activity as monotherapy. Samples were collected to explore potential biomarkers. Results: 13 patients (~17.8% of evaluable patients) had a clinical benefit up to cycle 6 (PR, SD), with the majority experiencing a decrease in systemic S1P levels and an increase in C18 levels. 8 patients (~11% of evaluable patients) had PFS > 6 months, with 2 patients still on study six years after enrollment. Analysis of plasma samples also revealed an increase in anti-tumoral cytokines (IFNg, TNFa, IL-2) and a decrease in pro-tumoral ones (IL-6, 8, 10). Among patients with PFS > 6 months, there were 4 recurrent CRC patients (1PR, 3SD): 1 patient had a PFS of ~12 months, 2 of ~18 months, and 1 is still on study after 6 years. Conclusions: Results of this Phase 1 study in heavily pretreated patients show BXQ-350 was well tolerated and seem to generate a clinical benefit in CRC patients via modulation of S1P and ceramides. A phase 2 trial of BXQ-350 in combination with FOLFOX/Bevacizumab in newly diagnosed mCRC is on-going with plans to further investigate this novel mechanism of action. Clinical trial information: 02859857 .

Deciphering the role of platelets in severe allergy by an integrative omics approach.

Mechanisms causing the onset and perpetuation of inflammation in severe allergic patients remain unknown. Our previous studies suggested that severe allergic inflammation is linked to platelet dysfunction. Platelet-rich plasma (PRP) and platelet-poor plasma (PPP) samples were obtained by platelet-apheresis from severe (n= 7) and mild (n= 10) allergic patients and nonallergic subjects (n= 9) to perform platelet lipidomics by liquid chromatography coupled to mass spectrometry (LC-MS) and RNA-seq analysis. Significant metabolites and transcripts were used to identify compromised biological pathways in the severe phenotype. Platelet and inflammation-related proteins were quantified by Luminex. Platelets from severe allergic patients were characterized by high levels of ceramides, phosphoinositols, phosphocholines, and sphingomyelins. In contrast, they showed a decrease in eicosanoid precursor levels. Biological pathway analysis performed with the significant lipids revealed the alteration of phospholipases, calcium-dependent events, and linolenic metabolism. RNAseq confirmed mRNA overexpression of genes related to platelet activation and arachidonic acid metabolism in the severe phenotypes. Pathway analysis indicated the alteration of NOD, MAPK, TLR, TNF, and IL-17 pathways in the severe phenotype. P-Selectin and IL-17AF proteins were increased in the severe phenotype. This study demonstrates that platelet lipid, mRNA, and protein content is different according to allergy severity. These findings suggest that platelet load is a potential source of biomarkers and a new chance for therapeutic targets in severe inflammatory pathologies.

Ceramides from Sea Red Rice Bran Improve Health Indicators and Increase Stress Resistance of Caenorhabditis elegans through Insulin/IGF-1 Signaling (IIS) Pathway and JNK-1.

The antiaging effects of sea red rice bran in vivo, a new saline-tolerant sea rice byproduct containing high levels of ceramides (Cers), remain unknown. This study aimed to explore the antiaging effects exerted by Cers from sea red rice bran on Caenorhabditis elegans, assess its health indicators as well as tolerance, and then reveal the mechanism of action of Cers in prolonging the mean life span through genetic studies. The results indicated that the mean life span of Cers-treated C. elegans were dose-dependent in the range of 0.10-0.50 mg/mL. Additionally, Cers improved nematode motility, reduced lipofuscin accumulation, and enhanced resistance to heat stress and antioxidant enzyme activity. Genetic studies showed that Cers treatment had altered nematode gene expression. In addition, insulin/IGF-1 and jnk-1/mitogen-activated protein kinase (MAPK) signaling pathways successfully demonstrated the longevity effects of Cers intake. In short, these results suggest that Cers enhance the resistance of C. elegans and prolong its life span.

PMON209 Ceramides Predict Metabolic Response to Metformin in Women with PCOS

Abstract Polycystic ovarian syndrome (PCOS) is a complex disorder in which metabolic abnormalities are associated with reproductive dysfunction. Women with PCOS have been shown to have increased ceramide concentrations with the obese, insulin resistant phenotype having even higher levels. Ceramides modulate insulin signaling, promoting insulin resistance, and are markers of diabetes risk and cardiovascular mortality. Previous studies demonstrate that treating metabolic abnormalities of PCOS with metformin improved glucose effectiveness, caused weight loss, and restored ovulation in 61% of women after 12 weeks. However, these metabolic improvements did not explain improved ovulation experienced by some women. Hypothesis We hypothesized that in women with PCOS, baseline ceramide, diacylglycerol (DAG) and triacylyglycerol (TAG) concentrations are associated with an improved metabolic response to metformin.Subjects: Women (n=29), aged 29±5 years and diagnosed with PCOS by the NIH criteria were studied. Methods Individuals underwent an intravenous glucose tolerance test (IVGTT) and hCG-stimulation before and after 12-weeks of treatment with metformin (1500 mg per day). Metabolic responders were defined by improved glucose effectiveness after metformin treatment. Results Among predominantly white women with an average body mass index 29.4±6.1 kg/m2, 12-weeks of metformin resulted in weight loss (-1.7±2.6 kg, p<0.01) and a reduction in BMI (-0.6±0.9 kg/m2, p<0.01) with no change in HbA1c (5.5%±0.3 vs 5.5%±0.3, p=0.7). The concentrations of ceramides with acyl chain length at 22 and 24 (C22 and C24), total ceramides, dihydroceramides (C16: 0), C18: 2, DAG, dihydrosphingomyelin (DHSM), and TAG decreased after metformin treatment (p<0.05). Baseline total dihydroceramides (C16: 0) and DHSM were lower in metabolic responders compared to metabolic non-responders (C16: 0 172±11 vs 232±14 pmol/ml, p<0.01; DHSM 36650±2642 vs 48842±3379 pmol/ml, p<0.01). Total C16: 0 concentrations of <204 pmol/ml was 83% sensitive (AUC 0.79, p<0.01) and total DHSM concentrations of <51705 pmol/ml was 100% sensitive (AUC 0.73, p=0.02) in predicting improved metabolic response to metformin, as measured by IVGTT. After adjusting for multiple comparisons, baseline DAG and TAG concentrations were associated with baseline ß-cell function (DAG r2=0.47, p<0.01; TAG r2=0.32, p<0.01), basal insulin concentrations (DAG r2=0.48, p<0.01; TAG r2=0.33, p<0.01) and decreased insulin sensitivity (DAG r2= 0.45, p<0.01; TAG r2=0.3,p<0.01). Baseline ceramide concentrations were not associated with improved ovulation. Conclusion Ceramide concentrations predict metabolic disruption and lower levels are associated with a beneficial metabolic response to metformin in women with PCOS. Based on the known association between higher ceramide levels and type 2 diabetes, the data suggest that metformin improves metabolic parameters in women with mild metabolic derangements but not in those with severe insulin resistance. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

The Use of Ceramides to Predict Metabolic Response to Metformin in Women With PCOS.

ContextPolycystic ovarian syndrome (PCOS) is a complex disorder in which metabolic abnormalities are associated with reproductive dysfunction. Women with PCOS have increased ceramide concentrations. Previous studies demonstrated that treating metabolic abnormalities of PCOS with metformin improved glucose effectiveness after 12 weeks.ObjectiveWe evaluated whether, in women with PCOS, lower baseline ceramide, diacylglycerol (DAG), and triacylglycerol (TAG) concentrations were associated with improved metabolic response to metformin.MethodsWomen (n = 29), aged 29 ± 5 years and diagnosed with PCOS by the NIH criteria underwent an intravenous glucose tolerance test (IVGTT) before and after 12-week treatment with metformin (1500 mg per day). Metabolic responders were defined by improved glucose effectiveness, specifically, the ability of glucose to stimulate uptake and suppress production, after metformin treatment.ResultsTwelve weeks of metformin resulted in weight loss (−1.7 ± 2.6 kg, P < 0.01) and a reduction in BMI (−0.6 ± 0.9 kg/m2, P < 0.01) with no change in HbA1c. The concentrations of Cer(d18:1/22:0), Cer(d18:1/24:0), total ceramides, total Cer(d16:0), total Cer(d18:2), DAG, dihydrosphingomyelin (DHSM), and TAG decreased after metformin treatment (P < 0.05). Baseline total Cer(d16:0) concentration <204.1 pmol/mL was 82% sensitive (AUC 0.72, P = 0.03) and total DHSM concentration <32237 pmol/mL was 100% specific (AUC 0.73, P = 0.03) in predicting improved metabolic response to metformin, as measured by IVGTT.ConclusionLower total Cer(16:0) and DHSM concentrations are associated with a beneficial metabolic response to metformin in women with PCOS. Based on the known association between higher ceramide levels and type 2 diabetes, the data suggest that metformin improves metabolic parameters in women with mild metabolic derangements.

Accumulation of cholesterol, triglycerides and ceramides in hepatocellular carcinomas of diethylnitrosamine injected mice

BackgroundDysregulated lipid metabolism is critically involved in the development of hepatocellular carcinoma (HCC). The respective metabolic pathways affected in HCC can be identified using suitable experimental models. Mice injected with diethylnitrosamine (DEN) and fed a normal chow develop HCC. For the analysis of the pathophysiology of HCC in this model a comprehensive lipidomic analysis was performed.MethodsLipids were measured in tumor and non-tumorous tissues by direct flow injection analysis. Proteins with a role in lipid metabolism were analysed by immunoblot. Mann-Whitney U-test or paired Student´s t-test were used for data analysis.ResultsIntra-tumor lipid deposition is a characteristic of HCCs, and di- and triglycerides accumulated in the tumor tissues of the mice. Peroxisome proliferator-activated receptor gamma coactivator 1 alpha, lipoprotein lipase and hepatic lipase protein were low in the tumors whereas proteins involved in de novo lipogenesis were not changed. Higher rates of de novo lipogenesis cause a shift towards saturated acyl chains, which did not occur in the murine HCC model. Besides, LDL-receptor protein and cholesteryl ester levels were higher in the murine HCC tissues. Ceramides are cytotoxic lipids and are low in human HCCs. Notably, ceramide levels increased in the murine tumors, and the simultaneous decline of sphingomyelins suggests that sphingomyelinases were involved herein. DEN is well described to induce the tumor suppressor protein p53 in the liver, and p53 was additionally upregulated in the tumors.ConclusionsCeramides mediate the anti-cancer effects of different chemotherapeutic drugs and restoration of ceramide levels was effective against HCC. High ceramide levels in the tumors makes the DEN injected mice an unsuitable model to study therapies targeting ceramide metabolism. This model is useful for investigating how tumors evade the cytotoxic effects of ceramides.

Ceramide synthase TLCD3B is a novel gene associated with human recessive retinal dystrophy

PurposePrevious studies suggest that ceramide is a proapoptotic lipid as high levels of ceramides can lead to apoptosis of neuronal cells, including photoreceptors. However, no pathogenic variant in ceramide synthases has been identified in human patients and knockout of various ceramide synthases in mice has not led to photoreceptor degeneration.MethodsExome sequencing was used to identify candidate disease genes in patients with vision loss as confirmed by standard evaluation methods, including electroretinography (ERG) and optical coherence tomography. The vision loss phenotype in mice was evaluated by ERG and histological analyses.ResultsHere we have identified four patients with cone-rod dystrophy or maculopathy from three families carrying pathogenic variants in TLCD3B. Consistent with the phenotype observed in patients, the Tlcd3bKO/KO mice exhibited a significant reduction of the cone photoreceptor light responses, thinning of the outer nuclear layer, and loss of cone photoreceptors across the retina.ConclusionOur results provide the first link between loss-of-function variants in a ceramide synthase gene and human retinal dystrophy. Establishment of the Tlcd3b knockout murine model, the first in vivo photoreceptor cell degeneration model due to loss of a ceramide synthase, will provide a unique opportunity in probing the role of ceramide in survival and function of photoreceptor cells.

Plasma Ceramides and Risk of Impaired Lower-Extremity Function in Older Adults: A Nested Case-Control Study.

Higher levels of ceramides have been linked to several chronic diseases; also there is emerging cross-sectional evidence that ceramides are associated with lower physical functioning. This research assessed for the first time the prospective relationship between ceramide species and impaired lower-extremity function (ILEF) in older adults. Case-control study with 43 cases of ILEF and 86 age- and sex-matched controls, which was nested in the Seniors-ENRICA cohort of community-dwelling older adults. Incident ILEF from 2015 to 2017 was ascertained with the Short Physical Performance Battery. In 2015, 27 ceramide species were measured in plasma by liquid chromatography-tandem mass spectrometry. Conditional logistic regression models were used to assess the longitudinal relationship between ceramides concentration and incidence of ILEF. After adjusting for education level, body mass index, alcohol and total energy intake, physical activity, and presence of chronic conditions, some ceramide species were related to 2-year incidence of ILEF. Specifically, the odds ratios of ILEF per 1-SD increase in ceramide concentration were: 1.66 [95% CI = (1.03, 2.68)] for ceramide C14:0, 1.61 (1.00, 2.59) for ceramide C16:0, and 1.64 (1.03, 2.60) for ceramide C16:1 (n-7). In the case of ceramides C16:0 and C16:1 (n-7), a stronger relationship was found in those with a higher body mass index; systolic blood pressure could also mediate the relationship between ceramide C16:1 (n-7) and ILEF (p for interaction = .03). Higher plasma levels of ceramides C14:0, C16:0, and C16:1 (n-7) are associated with higher risk of ILEF, and might serve as risk markers for functional decline in older adults.

Sphingolipids and plasma membrane hydrolases in human primary bronchial cells during differentiation and their altered patterns in cystic fibrosis

Human primary bronchial epithelial cells differentiated in vitro represent a valuable tool to study lung diseases such as cystic fibrosis (CF), an inherited disorder caused by mutations in the gene coding for the Cystic Fibrosis Transmembrane Conductance Regulator. In CF, sphingolipids, a ubiquitous class of bioactive lipids mainly associated with the outer layer of the plasma membrane, seem to play a crucial role in the establishment of the severe lung complications. Nevertheless, no information on the involvement of sphingolipids and their metabolism in the differentiation of primary bronchial epithelial cells are available so far. Here we show that ceramide and globotriaosylceramide increased during cell differentiation, whereas glucosylceramide and gangliosides content decreased. In addition, we found that apical plasma membrane of differentiated bronchial cells is characterized by a higher content of sphingolipids in comparison to the other cell membranes and that activity of sphingolipids catabolic enzymes associated with this membrane results altered with respect to the total cell activities. In particular, the apical membrane of CF cells was characterized by high levels of ceramide and glucosylceramide, known to have proinflammatory activity. On this basis, our data further support the role of sphingolipids in the onset of CF lung pathology.

Unregulated Sphingolipid Biosynthesis in Gene-Edited Arabidopsis ORM Mutants Results in Nonviable Seeds with Strongly Reduced Oil Content.

Orosomucoid-like proteins (ORMs) interact with serine palmitoyltransferase (SPT) to negatively regulate sphingolipid biosynthesis, a reversible process critical for balancing the intracellular sphingolipid levels needed for growth and programmed cell death. Here, we show that ORM1 and ORM2 are essential for life cycle completion in Arabidopsis (Arabidopsis thaliana). Seeds from orm1 -/- orm2 -/- mutants, generated by crossing CRISPR/Cas9 knockout mutants for each gene, accumulated high levels of ceramide, indicative of unregulated sphingolipid biosynthesis. orm1 -/- orm2 -/- seeds were nonviable, displayed aberrant embryo development, and had >80% reduced oil content versus wild-type seeds. This phenotype was mimicked in Arabidopsis seeds expressing the SPT subunit LCB1 lacking its first transmembrane domain, which is critical for ORM-mediated regulation of SPT. We identified a mutant for ORM1 lacking one amino acid (Met-51) near its second transmembrane domain that retained its membrane topology. Expressing this allele in the orm2 background yielded plants that did not advance beyond the seedling stage, hyperaccumulated ceramides, and showed altered organellar structures and increased senescence- and pathogenesis-related gene expression. These seedlings also showed upregulated expression of genes for sphingolipid catabolic enzymes, pointing to additional mechanisms for maintaining sphingolipid homeostasis. ORM1 lacking Met-51 had strongly impaired interactions with LCB1 in a yeast (Saccharomyces cerevisiae) model, providing structural clues about regulatory interactions between ORM and SPT.

Race disparity in blood sphingolipidomics associated with lupus cardiovascular comorbidity.

Systemic lupus erythematous (SLE) is a chronic multi-organ autoimmune disease. Genetic and environmental factors contribute to disease onset and severity. Sphingolipids are signaling molecules involved in regulating cell functions and have been associated with multiple genetic disease processes. African-Americans are more likely to suffer from SLE morbidity than Whites. The Medical University of South Carolina has banked plasma samples from a well-characterized lupus cohort that includes African-Americans and Whites. This study examined the influence of race on plasma sphingolipid profiles in SLE patients and association of sphingolipid levels with comorbid atherosclerosis and SLE disease activity. Mass spectrometry revealed that healthy African-Americans had higher sphingomyelin levels and lower lactosylcermide levels compared to healthy Whites. SLE patients, irrespective of race, had higher levels of ceramides, and sphingoid bases (sphingosine and dihydrosphingosine) and their phosphates compared to healthy subjects. Compared to African-American controls, African-American SLE patients had higher levels of ceramides, hexosylceramides, sphingosine and dihydrosphingosine 1-phosphate. Compared to White controls, White SLE patients exhibited higher levels of sphingoid bases and their phosphates, but lower ratios of C16:0 ceramide/sphingosine 1-phosphate and C24:1 ceramide/sphingosine 1-phosphate. White SLE patients with atherosclerosis exhibited lower levels of sphingoid bases compared to White SLE patients without atherosclerosis. In contrast, African-American SLE patients with atherosclerosis had higher levels of sphingoid bases and sphingomyelins compared to African-American SLE patients without atherosclerosis. Compared to White SLE patients with atherosclerosis, African-American SLE patients with atherosclerosis had higher levels of select sphingolipids. Plasma levels of sphingosine, C16:0 ceramide/sphingosine 1-phosphate ratio and C24:1 ceramide/sphingosine 1-phosphate ratio significantly correlated with SLEDAI in the African-American but not White SLE patients. The C16:0 ceramide/sphingosine 1-phosphate ratio in SLE patients, and levels of C18:1 and C26:1 lactosylcermides, C20:0 hexosylceramide, and sphingoid bases in SLE patients with atherosclerosis could be dependent on race. Further ethnic studies in SLE cohorts are necessary to verify use of sphingolipidomics as complementary diagnostic tool.

Elevated serum ceramides are linked with obesity-associated gut dysbiosis and impaired glucose metabolism.

Low gut microbiome richness is associated with dyslipidemia and insulin resistance, and ceramides and other sphingolipids are implicated in the development of diabetes. Determine whether circulating sphingolipids, particularly ceramides, are associated with alterations in the gut microbiome among obese patients with increased diabetes risk. This was a cross-sectional and longitudinal retrospective analysis of a dietary/weight loss intervention. Fasted serum was collected from 49 participants (41 women) and analyzed by HPLC-MS/MS to quantify 45 sphingolipids. Shotgun metagenomic sequencing of stool was performed to profile the gut microbiome. Confirming the link to deteriorated glucose homeostasis, serum ceramides were positively correlated with fasting glucose, but inversely correlated with fasting and OGTT-derived measures of insulin sensitivity and β-cell function. Significant associations with gut dysbiosis were demonstrated, with SM and ceramides being inversely correlated with gene richness. Ceramides with fatty acid chain lengths of 20-24 carbons were the most associated with low richness. Diet-induced weight loss, which improved gene richness, decreased most sphingolipids. Thirty-one MGS, mostly corresponding to unidentified bacteria species, were inversely correlated with ceramides, including a number of Bifidobacterium and Methanobrevibacter smithii. Higher ceramide levels were also associated with increased metagenomic modules for lipopolysaccharide synthesis and flagellan synthesis, two pathogen-associated molecular patterns, and decreased enrichment of genes involved in methanogenesis and bile acid metabolism. This study identifies an association between gut microbiota richness, ceramides, and diabetes risk in overweight/obese humans, and suggests that the gut microbiota may contribute to dysregulation of lipid metabolism in metabolic disorders.

Niemann-Pick Type A Disease: Behavior of Neutral Sphingomyelinase and Vitamin D Receptor.

Sphingomyelinase (SMase) is responsible for the breakdown of sphingomyelin (SM) with production of ceramide. The absence of acid sphingomyelinase (aSMase) causes abnormal synapse formation in Niemann-Pick type A (NPA) disease. Because high levels of ceramide in the NPA brain were demonstrated, the involvement of other SMases were supposed. In the present study we focused the attention on the neurogenic niches in the hippocampal gyrus dentatus (GD), a brain structure essential for forming cohesive memory. We demonstrated for the first time the increase of (Sex determining region Y)-box 2 (SOX2), and the down-regulation of glial fibrillary acidic protein (GFAP) NPA mice GD. Moreover, we found that the expression of Toll like receptors (TLRs), was increased in NPA mice, particularly TLR2, TLR7, TLR8 and TLR9 members. Although no significant change in neutral sphingomyelinase (nSMase) gene expression was detected in the NPA mice hippocampus of, protein levels were enhanced, probably because of the slower protein degradation rate in this area. Many studies demonstrated that vitamin D receptor (VDR) is expressed in the hippocampus GD. Unexpectedly, we showed that NPA mice exhibited VDR gene and protein expression up-regulation. In summary, our study suggests a relation between hippocampal cell differentiation defect, nSMase and VDR increase in NPA mice.