Ceramide Profile Research Articles

698 Stratum corneum ceramide profiles provide reliable indicators of remission and potential flares in atopic dermatitis

698 Stratum corneum ceramide profiles provide reliable indicators of remission and potential flares in atopic dermatitis

Plasma metabolomic signatures of dual decline in memory and gait in older adults

Older adults experiencing dual decline in memory and gait have greater dementia risk than those with memory or gait decline only, but mechanisms are unknown. Dual decline may indicate specific pathophysiological pathways to dementia which can be reflected by circulating metabolites. We compared longitudinal changes in plasma metabolite biomarkers of older adults with and without dual decline in the Baltimore Longitudinal Study of Aging (BLSA). Participants were grouped into 4 phenotypes based on annual rates of decline in verbal memory and gait speed: no decline in memory or gait, memory decline only, gait decline only, and dual decline. Repeated measures of plasma metabolomics were measured by biocrates p500 kit during the same time of memory and gait assessments. In BLSA, 18 metabolites differed across groups (q-value < 0.05). Metabolites differentially abundant were enriched for lysophosphatidylcholines (lysoPC C18:0,C16:0,C17:0,C18:1,C18:2), ceramides (d18:2/24:0,d16:1/24:0,d16:1/23:0), and amino acids (glycine) classes. Compared to no decline, the dual decline group showed greater declines in lysoPC C18:0, homoarginine synthesis, and the metabolite module containing mostly triglycerides, and showed a greater increase in indoleamine 2,3-dioxygenase (IDO) activity. Metabolites distinguishing dual decline and no decline groups were implicated in metabolic pathways of the aminoacyl-tRNA biosynthesis, valine, leucine and isoleucine biosynthesis, histidine metabolism, and sphingolipid metabolism. Older adults with dual decline exhibit the most extensive alterations in metabolic profiling of lysoPCs, ceramides, IDO activity, and homoarginine synthesis. Alterations in these metabolites may indicate mitochondrial dysfunction, compromised immunity, and elevated burden of cardiovascular and kidney pathology.

Molecular species profiles of plasma ceramides in different clinical types of X-linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy (X-ALD) is a genetic disorder associated with peroxisomal dysfunction. Patients with this rare disease accumulate very long-chain fatty acids (VLCFAs) in their bodies because of impairment of peroxisomal VLCFA ?-oxidation. Several clinical types of X-ALD, ranging from mild (axonopathy in the spinal cord) to severe (cerebral demyelination), are known. However, the molecular basis for this phenotypic variability remains largely unknown. In this study, we determined plasma ceramide (CER) profile using liquid chromatography-tandem mass spectrometry. We characterized the molecular species profile of CER in the plasma of patients with mild (adrenomyeloneuropathy;AMN) and severe (cerebral) X-ALD. Eleven X-ALD patients (five cerebral, five AMN, and one carrier) and 10 healthy volunteers participated in this study. Elevation of C26:0 CER was found to be a common feature regardless of the clinical types. The level of C26:1 CER was significantly higher in AMN but not in cerebral type, than that in healthy controls. The C26:1 CER level in the cerebral type was significantly lower than that in the AMN type. These results suggest that a high level of C26:0 CER, along with a control level of C26:1 CER, is a characteristic feature of the cerebral type X-ALD. J. Med. Invest. 70 : 403-410, August, 2023.

Inhibition of Ceramide Synthesis Attenuates Chronic Ethanol Induced Cardiotoxicity by Restoring Lysosomal Function and Reducing Necroptosis.

Chronic alcohol misuse could cause alcoholic cardiomyopathy (ACM), and the specific mechanisms remained largely unknown. In this study, we aimed to explore the effects of endogenous ceramides on chronic ethanol-induced myocardial injury or cell loss (e.g. necroptosis). We established chronic alcohol intoxication models in vivo (male C57BL/6 mice) and in vitro (H9c2 cardiomyoblasts). The ceramide profiles were analyzed in mice myocardium and cultured cardiomyocytes. Further research on the role of ceramides and underlying signaling pathways was carried out in H9c2 cells. The ceramide profiles analysis revealed increased long and very long-chain ceramides in alcoholic myocardium and ethanol-treated cardiomyocytes. Next, we proved that endogenous ceramide inhibition could reduce necroptosis and alleviate cardiomyocytes injury as suggested by decreased levels of p-RIPK1, p-RIPK3 and p-MLKL proteins and cardiac injury factors expression. Furthermore, we found that lysosomal dysfunction also contributed to alcohol-induced cardiac damage and inhibiting ceramide biosynthesis could repaired this to some extent. Cells studies with exogenous C6 ceramide confirmed the pleotropic roles of ceramide in myocardial damage by causing both necroptosis and lysosomal dysfunction. Finally, our data suggested that lysosomal dysfunction could sensitize cardiomyocytes to induction of necroptosis due to the restriction on degradation of RIPK1/RIPK3 proteins. In conclusion, chronic ethanol treatment boosted myocardial ceramide synthesis in animal hearts and cultured cardiomyocytes. Moreover, ceramides exerted crucial roles in the intrinsic signaling pathways of alcohol-induced cardiotoxicity. Targeting ceramide biosynthesis to simultaneously attenuate necroptosis and lysosomal dysfunction might be a novel strategy for preventing alcoholic cardiotoxicity.

Menopause induces changes to the stratum corneum ceramide profile, which are prevented by hormone replacement therapy

The menopause can lead to epidermal changes that are alleviated by hormone replacement therapy (HRT). We hypothesise that these changes could relate to altered ceramide production, and that oestrogen may have a role in keratinocyte ceramide metabolism. White Caucasian women were recruited into three groups: pre-menopausal (n = 7), post-menopausal (n = 11) and post-menopausal taking HRT (n = 10). Blood samples were assessed for hormone levels, transepidermal water loss was measured to assess skin barrier function, and stratum corneum lipids were sampled from photoprotected buttock skin. Ceramides and sphingomyelins were analysed by ultraperformance liquid chromatography with electrospray ionisation and tandem mass spectrometry. Post-menopausal stratum corneum contained lower levels of ceramides, with shorter average length; changes that were not evident in the HRT group. Serum oestradiol correlated with ceramide abundance and length. Ceramides had shorter sphingoid bases, indicating altered de novo ceramide biosynthesis. Additionally, post-menopausal women had higher sphingomyelin levels, suggesting a possible effect on the hydrolysis pathway. Treatment of primary human keratinocytes with oestradiol (10 nM) increased production of CER[NS] and CER[NDS] ceramides, confirming an effect of oestrogen on cutaneous ceramide metabolism. Taken together, these data show perturbed stratum corneum lipids post-menopause, and a role for oestrogen in ceramide production.

Serum Ceramide Species Are Associated with Liver Cirrhosis and Viral Genotype in Patients with Hepatitis C Infection.

Hepatitis C virus (HCV) infection affects ceramide metabolism, and, here, we have evaluated associations of eight serum ceramide species with viral load, viral genotype, and disease markers in 178 patients with chronic HCV. In this cohort, ceramide d18:1;O2/16:0 was higher in the serum of the 20 diabetic patients compared to the patients without this complication. Moreover, ceramide d18:1;O2/24:0 was negatively correlated with age. Of note, all but ceramide d18:1;O2/16:0 and 26:0 were diminished in the serum of patients with liver cirrhosis and, with the exception of ceramide d18:1;O2/16:0, were negatively correlated with the model for end-stage liver disease (MELD) score. Most of the serum ceramides are carried in low-density lipoprotein (LDL), which rises following effective direct-acting antiviral (DAA) therapy. Ceramide d18:1;O2/24:0 recovered in parallel with LDL, whereas ceramide d18:1;O2/18:0 declined. Genotype-3-infected patients had the lowest ceramide levels, which were comparable to other genotypes after DAA treatment. Notably, ceramide d18:1;O2/23:0 and 24:0 were negatively correlated with the MELD score in patients with liver cirrhosis at the end of DAA therapy. Long-chain (LC) ceramides show adverse effects, whereas very-long-chain (VL) species have protective functions in the liver. The ratio of VL/LC ceramides was higher in non-cirrhosis patients than cirrhosis patients and further increased at the end of therapy in this subgroup. In summary, our study shows that serum ceramide levels are related to liver cirrhosis and viral genotype. Whether the more favorable serum ceramide profile in non-cirrhosis patients, before and after DAA therapy, is of pathophysiological importance needs further investigation.

Ceramide profiling of stratum corneum in Sjögren–Larsson syndrome

BackgroundSjögren–Larsson syndrome (SLS) is a neurocutaneous disorder whose causative gene is the fatty aldehyde dehydrogenase ALDH3A2 and of which ichthyosis is the major skin symptom. The stratum corneum contains a variety of ceramides, among which ω-O-acylceramides (acylceramides) and protein-bound ceramides are essential for skin permeability barrier formation. ObjectivesTo determine the ceramide classes/species responsible for SLS pathogenesis and the enzymes that are impaired in SLS. MethodsGenomic DNA was collected from peripheral blood samples from an SLS patient and her parents, and whole-genome sequencing and Sanger sequencing were performed. Lipids were extracted from stratum corneum samples from the SLS patient and healthy volunteers and subjected to ceramide profiling via liquid chromatography coupled with tandem mass spectrometry. ResultsA duplication (c.55_130dup) and a missense mutation (p.Lys447Glu) were found in the patient’s ALDH3A2 gene. The patient had reduced levels of all acylceramide classes, with total acylceramide levels at 25 % of healthy controls. Reductions were also observed for several nonacylated ceramides: ceramides with phytosphingosine or 6-hydroxysphingosine in the long-chain base moiety were reduced to 24 % and 41 % of control levels, respectively, and ceramides with an α-hydroxy fatty acid as the fatty acid moiety were reduced to 29 %. The fatty acid moiety was shortened in many nonacylated ceramide classes. ConclusionThese results suggest that reduced acylceramide levels are a primary cause of the ichthyosis symptoms of SLS, but reductions in other ceramide classes may also be involved.

Stratum Corneum Ceramide Profiles Provide Reliable Indicators of Remission and Potential Flares in Atopic Dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin disease. Prevention of exacerbation of AD is a crucial issue for all physicians. However, exacerbation of AD often is seen during reduction of AD treatment, even with appropriate follow-up by tapered topical corticosteroids and daily topical moisturizers, indicating the need for good indicators of AD remission. We hypothesized that the presence of mutations in FLG or the stratum corneum ceramide profile on AD remission phase may predict the ease of AD exacerbation. This study examined the differences in the frequency of FLG mutations or stratum corneum ceramide profiles (stratum corneum levels and carbon chain length for 11 ceramide classes [ceramides containing nonhydroxy fatty acids and dihydrosphingosines; nonhydroxy fatty acids and sphingosines; nonhydroxy fatty acids and 6-hydroxysphingosines; nonhydroxy fatty acids and phytosphingosines; a-hydroxy fatty acids and dihydrosphingosines; a-hydroxy fatty acids and sphingosines; a-hydroxy fatty acids and 6-hydroxysphingosines; a-hydroxy fatty acids and phytosphingosines; ester-linked fatty acids, o-hydroxy fatty acids, and sphingosines; ester-linked fatty acids, o-hydroxy fatty acids, and 6-hydroxysphingosines; and ester-linked fatty acids, o-hydroxyfatty acids, and phytosphingosines]) at AD remission phase between the two AD study groups: subsequent exacerbation (‒) and (+) of AD. The frequency of FLG mutations did not differ between the study groups. On the other hand, the carbon chain lengths of ceramides containing nonhydroxy fatty acids and dihydrosphingosines, nonhydroxy fatty acids and sphingosines, and nonhydroxy fatty acids and 6-hydroxysphingosines were shorter in the exacerbated AD group than in the maintained-AD group. Thus, the stratum corneum ceramide profile at the remission phase of AD is a potential biomarker, predicting the likelihood of substantial AD remission or subsequent AD exacerbation.

Differences in the plasma phospholipid profile of patients infected with tick-borne encephalitis virus and co-infected with bacteria

Tick-borne encephalitis (TBE) is an infectious viral disease, the pathogenesis of which is still not fully understood. Additionally, TBE can be complicated by co-infections with various bacteria that are also transmitted by ticks, which can affect the proper diagnosis and treatment. Therefore, the aim of the study was to evaluate changes in the plasma phospholipid (PL) and ceramide (CER) profile of patients with TBE and patients with bacterial co-infection (B. burgdorferi or A. phagocytophilum) in relation to healthy subjects. For this purpose, a high-resolution LC-QTOF-MS/MS platform as well as univariate and multivariate statistics were used. The results of this study showed that the levels of phosphatidylcholines (PC) and lysophosphatidylcholines (LPC) species were increased in the plasma of patients with TBE and patients with TBE co-infected with bacteria. On the other hand, observed differences in the content of phosphoethanolamines (PE) and sphingomyelins (SM) make it possible to distinguish TBE patients from patients with co-infections. The opposite direction of changes was also observed in the CER content. This study showed significant modifications to the metabolic pathways of linoleic (LA) and arachidonic acid (AA), as confirmed by the quantitative analysis of these fatty acids. The obtained results allow to distinguish the pathomechanism of TBE from TBE with bacterial co-infection, and consequently may improve the diagnostic process and enable more efficient pharmacotherapy against both pathogens.

Ectopic accumulation of ceramide in cardiomyocytes modulates alcoholic cardiomyopathy via the TLR4-dependent pathway.

Excessive alcohol consumption predisposes drinkers to develop alcoholic cardiomyopathy. Although cardiomyocyte loss is the hallmark of cardiomyopathy, the underlying mechanism remains elusive. This study examined the potential mechanism of alcohol-induced cardiomyocyte death in a mouse model of alcoholic cardiomyopathy. We established the alcoholic cardiomyopathy mouse model using C57BL/6J mice and confirmed it via echocardiography and histological examination. The cardiac ceramide content and profile were analyzed with a triple-quadrupole mass spectrometer. The molecular mechanism underlying the accumulation of ceramide due to chronic alcohol consumption and ceramide-induced cardiomyocyte death were investigated by in vivo and in vitro models. Finally, we established a TLR4 mutation model to explore the function of TLR4 in CH3/HeJ mice. Cardiac lipotoxicity that followed alcohol exposure resulted mainly in C16:0-, C18:0-, and C24:1-ceramide aggregation. Genes encoding the sphingosine hydrolysis enzymes (SMPD1 and SMPD2) rather than de novo synthetic biomarkers were markedly upregulated. Exogenous ceramide mimics (C6-ceramide) werenderlying the accumulation of ceramide observed to cause H9C2 cardiomyocyte-like cell death, which was consistent with results under palmate acid (PA) treatment. As a ceramide precursor, PA induces intracellular ceramide generation through TLR4 signaling, which can be abolished by an inhibitor of ceramide synthesis. Furthermore, mechanistic investigations demonstrated that pharmacological or genetic inhibition of TLR4 attenuated PA-induced cell death and corresponding ceramide production. Moreover, global mutation of TLR4 in CH3/HeJ mice significantly reduced the accumulation of C24:0, C24:1, OH_C24:1, and total ceramide following alcohol challenge. Our findings demonstrate that ceramide accumulation plays a crucial role in alcoholic cardiomyopathy, effects that are partially mediated through the TLR4-dependent pathway.

Ceramide Composition in Exosomes for Characterization of Glioblastoma Stem-Like Cell Phenotypes.

Glioblastoma (GBM) is one of the most malignant central nervous system tumor types. Comparative analysis of GBM tissues has rendered four major molecular subtypes. From them, two molecular subtypes are mainly found in their glioblastoma cancer stem-like cells (GSCs) derived in vitro: proneural (PN) and mesenchymal (MES) with nodular (MES-N) and semi-nodular (MES-SN) disseminations, which exhibit different metabolic, growth, and malignancy properties. Many studies suggest that cancer cells communicate between them, and the surrounding microenvironment, via exosomes. Identifying molecular markers that allow the specific isolation of GSC-derived exosomes is key in the development of new therapies. However, the differential exosome composition produced by main GSCs remains unknown. The aim of this study was to determine ceramide (Cer) composition, one of the critical lipids in both cells and their cell-derived exosomes, from the main three GSC phenotypes using mass spectrometry-based lipidomics. GSCs from human tissue samples and their cell-derived exosomes were measured using ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC/Q-TOF-MS) in an untargeted analysis. Complete characterization of the ceramide profile, in both cells and cell-derived exosomes from GSC phenotypes, showed differential distributions among them. Results indicate that such differences of ceramide are chain-length dependent. Significant changes for the C16 Cer and C24:1 Cer and their ratio were observed among GSC phenotypes, being different for cells and their cell-derived exosomes.

Alteration to the Skin Ceramide Profile Following Broad-Spectrum UV Exposure.

The epidermal stratum corneum (SC) lipid matrix, principally consisting of an equimolar ratio of ceramides, free fatty acids, and cholesterol, plays a crucial role in maintaining proper skin barrier function. Conditions which impair barrier integrity, such as in atopic dermatitis, correlate with the alternation of key ceramide subclasses and reduced chain length of acyl moieties. However, there is limited knowledge about the impact of unprotected repeat sun exposure on the skin lipid composition, especially ceramide profiles.This study investigated the effects of ultraviolet (UV) radiation on the ceramide profile using both an ex vivo skin and a clinical model. Lipidomic analysis of UV-exposed skin showed shifts to the composition of ceramide subclasses essential in repairing and strengthening the SC barrier (including CER1[EOS], CER3[NP], and CER6[AP]) and reduced very long-chain acyl moieties. Gene expression analysis and immunohistochemical staining of key enzymes (aSMase, DES1, CerS5, CerS3) suggested that lipid alterations can be attributed to changes within the ceramide biosynthesis process. Topical application of ceramide-containing suncare products help maintain SC-essential ceramide subclasses and proper ceramide chain length, demonstrating the importance of proper photoprotection to maintain healthy skin barrier and ceramide quality during daily sun exposure. J Drugs Dermatol. 2022;21(1):77-85. doi:10.36849/JDD.6331.

Alteration to the Skin Ceramide Profile Following Broad-Spectrum UV Exposure

The epidermal stratum corneum (SC) lipid matrix, principally consisting of an equimolar ratio of ceramides, free fatty acids, and cholesterol, plays a crucial role in maintaining proper skin barrier function. Conditions which impair barrier integrity, such as in atopic dermatitis, correlate with the alternation of key ceramide subclasses and reduced chain length of acyl moieties. However, there is limited knowledge about the impact of unprotected repeat sun exposure on the skin lipid composition, especially ceramide profiles.This study investigated the effects of ultraviolet (UV) radiation on the ceramide profile using both an ex vivo skin and a clinical model. Lipidomic analysis of UV-exposed skin showed shifts to the composition of ceramide subclasses essential in repairing and strengthening the SC barrier (including CER1[EOS], CER3[NP], and CER6[AP]) and reduced very long-chain acyl moieties. Gene expression analysis and immunohistochemical staining of key enzymes (aSMase, DES1, CerS5, CerS3) suggested that lipid alterations can be attributed to changes within the ceramide biosynthesis process. Topical application of ceramide-containing suncare products help maintain SC-essential ceramide subclasses and proper ceramide chain length, demonstrating the importance of proper photoprotection to maintain healthy skin barrier and ceramide quality during daily sun exposure. J Drugs Dermatol. 2022;21(1):77-85. doi:10.36849/JDD.6331Broad-Spectrum UV Exposure

Drug triggered pruritus, rash, papules, and blisters \u2013 is AGEP a clash of an altered sphingolipid-metabolism and lysosomotropism of drugs accumulating in the skin?

Rash, photosensitivity, erythema multiforme, and the acute generalized exanthematous pustulosis (AGEP) are relatively uncommon adverse reactions of drugs. To date, the etiology is not well understood and individual susceptibility still remains unknown. Amiodarone, chlorpromazine, amitriptyline, and trimipramine are classified lysosomotropic as well as photosensitizing, however, they fail to trigger rash and pruritic papules in all individuals. Lysosomotropism is a common charcteristic of various drugs, but independent of individuals. There is evidence that the individual ability to respond to external oxidative stress is crosslinked with the elongation of long-chain fatty acids to very long-chain fatty acids by ELOVLs. ELOVL6 and ELOVL7 are sensitive to ROS induced depletion of cellular NADPH and insufficient regeneration via the pentose phosphate pathway and mitochondrial fatty acid oxidation. Deficiency of NADPH in presence of lysosomotropic drugs promotes the synthesis of C16-ceramide in lysosomes and may contribute to emerging pruritic papules of AGEP. However, independently from a lysosomomotropic drug, severe depletion of ATP and NAD(P)H, e.g., by UV radiation or a potent photosensitizer can trigger likewise the collapse of the lysosomal transmembrane proton gradient resulting in lysosomal C16-ceramide synthesis and pruritic papules. This kind of papules are equally present in polymorphous light eruption (PMLE/PLE) and acne aestivalis (Mallorca acne). The suggested model of a compartmentalized ceramide metabolism provides a more sophisticated explanation of cutaneous drug adverse effects and the individual sensitivity to UV radiation. Parameters such as pKa and ClogP of the triggering drug, cutaneous fatty acid profile, and ceramide profile enables new concepts in risk assessment and scoring of AGEP as well as prophylaxis outcome.

How Ceramides Orchestrate Cardiometabolic Health-An Ode to Physically Active Living.

Cardiometabolic diseases (CMD) represent a growing socioeconomic burden and concern for healthcare systems worldwide. Improving patients’ metabolic phenotyping in clinical practice will enable clinicians to better tailor prevention and treatment strategy to individual needs. Recently, elevated levels of specific lipid species, known as ceramides, were shown to predict cardiometabolic outcomes beyond traditional biomarkers such as cholesterol. Preliminary data showed that physical activity, a potent, low-cost, and patient-empowering means to reduce CMD-related burden, influences ceramide levels. While a single bout of physical exercise increases circulating and muscular ceramide levels, regular exercise reduces ceramide content. Additionally, several ceramide species have been reported to be negatively associated with cardiorespiratory fitness, which is a potent health marker reflecting training level. Thus, regular exercise could optimize cardiometabolic health, partly by reversing altered ceramide profiles. This short review provides an overview of ceramide metabolism and its role in cardiometabolic health and diseases, before presenting the effects of exercise on ceramides in humans.

Changes in Phospholipid/Ceramide Profiles and Eicosanoid Levels in the Plasma of Rats Irradiated with UV Rays and Treated Topically with Cannabidiol.

Chronic UV radiation causes oxidative stress and inflammation of skin and blood cells. Therefore, in this study, we assessed the effects of cannabidiol (CBD), a natural phytocannabinoid with antioxidant and anti-inflammatory properties, on the phospholipid (PL) and ceramide (CER) profiles in the plasma of nude rats irradiated with UVA/UVB and treated topically with CBD. The results obtained showed that UVA/UVB radiation increased the levels of phosphatidylcholines, lysophospholipids, and eicosanoids (PGE2, TxB2), while downregulation of sphingomyelins led to an increase in CER[NS] and CER[NDS]. Topical application of CBD to the skin of control rats significantly upregulated plasma ether-linked phosphatidylethanolamines (PEo) and ceramides. However, CBD administered to rats irradiated with UVA/UVB promoted further upregulation of CER and PEo and led to significant downregulation of lysophospholipids. This was accompanied by the anti-inflammatory effect of CBD, manifested by a reduction in the levels of proinflammatory PGE2 and TxB2 and a dramatic increase in the level of anti-inflammatory LPXA4. It can therefore be suggested that topical application of CBD to the skin of rats exposed to UVA/UVB radiation prevents changes in plasma phospholipid profile resulting in a reduction of inflammation by reducing the level of LPE and LPC species and increasing antioxidant capacity due to upregulation of PEo species.

Decrease of ceramides with long-chain fatty acids in psoriasis: Possible inhibitory effect of interferon gamma on chain elongation.

Reportedly, decreases in fatty acid (FA) chain length of ceramide (CER) are associated with interferon-γ (IFN-γ), which shows increased expression in psoriasis. However, the underlying mechanism of this association remains unclear. Therefore, in this study, we aimed to clarify this association between FA chain length of CER, IFN-γ, and the major transcriptional factors involving psoriasis. CER profiling according to FA chain length and class was performed in murine epidermis (n=10 BALB/c mice topically treated with imiquimod, n=10 controls) and human stratum corneum (SC) (n=12 psoriasis, n=11 controls). The expression of lipid synthetic enzymes, including elongases (ELOVLs), in murine epidermis was also measured using RT-PCR. Furthermore, the association of IFN-γ with various enzymes and transcription factors involved in the generation of long-chain CERs was also investigated using in vitro keratinocyte. A significant decrease in the percentage of long-chain CERs was observed in psoriasis-like murine epidermis and human psoriatic SC. Additionally, the expression levels of ELOVL1, ELOVL4, and ceramide synthase3 (CerS3) were significantly decreased in psoriasis-like murine epidermis and IFN-γ-treated keratinocyte. There was also a significant decrease in the expression of transcriptional factors, including peroxisome proliferator-activated receptor (PPAR), in IFN-γ treated keratinocyte. Thus, it could be suggested that IFN-γ may regulate ELOVL and CerS levels by down-regulating the transcriptional factors. Additionally, given the possible involvement of PPARs or liver X receptor agonist in the CER elongation process, they may serve as potential therapeutic agents for lengthening the CER FAs in psoriasis.

New Insights on Hepatic De Novo Lipogenesis in Rat’s Fetus

ObjectivesAmong the macronutrients provided by the mothers to fetuses free fatty acids (FFA), particularly palmitic acid and glycerol cross the placental barrier in smaller proportions respect to glucose and amino acids, due to a minor placental permeability. It has already been suggested that during advanced gestation, fetal FA are mainly derived from de novo lipogenesis (DNL) in the fetal liver. Therefore, the aim of this study was to evaluate DNL metabolic biomarkers in fetuses of rat dams at gestational day (GD) 16, which represent the beginning of the third stage of gestation. Peculiarly, besides the usual lipid biomarkers of DNL, increase of PA and POA and the ratio PA/LA, we also evaluated whether C16:0 ceramide biosynthesis was enhanced by DNL thereby representing a novel biomarker of DNL. MethodsThe profile of FA and ceramides was measured by using LC-DAD and MS/MS in line in liver of rat dams sacrificed at GD16 and their fetuses. Differences between rat dams and their fetuses were determined by an Mann-Whitney unpaired test. ResultsOur results show that lipid metabolism in the liver of fetuses, when compared to those of their mother, was characterized by profound differences in the fatty acid profile, i.e., increased levels of the palmitic acid (16:0) (1.24 fold; p = 0.04) and its desaturase product palmitoleic acid (16:1-n7) (2.5 fold; p = 0.002) indicating an overactive DNL. Peculiarly, we found striking higher levels (30 fold; p = 0.02) in fetal liver respect to rat dams liver of C16:0 ceramide, while the other ceramides species didn’t increase significantly. ConclusionsOur data suggest that the 16:0 to form fetal C16:0 ceramide derives from DNL. C16:0 ceramide in adults is usually associated to impaired insulin signalling and energy homeostasis, and eventually to insulin resistance and type 2 diabetes. On the other hand, it has also been shown that C16:0 ceramide sustains lipogenesis, which may be functional to the increased fetal growth rate characteristic of the last gestational stage. Funding SourcesThis study was supported by grant from the Ministry of University and Research (MUR) - Proof of Concept 2018.

Sex-specific associations of ceramides with cardiopulmonary fitness in the general population

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): German Federal Ministry of Education &amp; Research (BMBF) Introduction According to the WHO 17.9 million people die because of cardiovascular diseases (CVD) each year, being the 3rd leading cause of death worldwide. Low cardiorespiratory fitness (CRF) is an important risk factor for CVD. Recent research showed that long-chain unsaturated ceramides are associated with higher risk of cardiovascular events, thus identifying ceramides as a potential novel and independent risk factor. However, not all ceramides are equal. We previously showed beneficial effects of very-long-chain ceramides (i.e. C24:0 and C24:0/C16:0 ratio) with higher concentrations being inversely associated with all-cause mortality and CVD events. Purpose We would like to investigate, if ceramides mediated their effects on developing CVD by affecting CRF. Therefore, we explored the association of three specific ceramides (C16:0, C22:0 and C24:0) and their ratios with different parameters of CRF. Methods We used data of the population-based Study of Health in Pomerania (SHIP-1) from North Germany (N: 1,247/men: 583, median age: 50.8 years/women: 664, median age: 50.2 years). Ceramides and CRF were assessed by LC/MS assay and symptom-limited cardiopulmonary exercise testing, respectively. VO2peak, VO2@AT, Wmax and respective indexing per kg body weight were used as outcomes. We used sex-stratified, multiple adjusted linear regression models. Participants with asthma, chronic lung disease, LVEF &amp;lt; 40% and cancer were excluded. Results In men, a 1-unit higher C24:0/C16:0 ratio was associated with higher VO2peak/kg (0.199 ml/min/kg [95% CI: 0.032, 0.365], P = 0.019), Wmax (1.368 W [0.033, 2.404], P = 0.010) and Wmax/kg (0.018 W/kg [0.007, 0.029], P = 0.002). In addition, a 1 µg/ml higher C24:0 concentration was related to greater Wmax/kg (0.054 W/kg [0.009, 0.099], P = 0.018). In women, a 1-unit greater C24:0/C16:0 ratio was associated with greater VO2peak (8.603 ml/min [0.019, 17.013], P = 0.045), VO2peak/kg (0.186 ml/min/kg [0.054, 0.319], P = 0.006), VO2@AT/kg (0.136 ml/min/kg [0.040, 0.231], P = 0.005) as well as higher Wmax/kg (0.015 W/kg [0.004, 0.026], P = 0.007). Furthermore, a 1 µg/ml higher C16:0 concentration was related to lower Wmax (-55.447 W [-101.775, -9.119], P = 0.019) and Wmax/kg (-0.736 W/kg [-1.341, -0.130], P = 0.017). Conclusions We report sex-specific associations between ceramides and CRF. In women, C24:0/C16:0 ratio was associated with more CRF parameters than in men. Furthermore, the single species C16:0 was significantly associated with lower maximal power in women only, whereas in men the single species C24:0 was significantly associated with higher maximal power. The positive association of the C24:0/C16:0 ratio with maximal CRF capacity is in agreement with previous findings of beneficial effects on the risk for CVD events and mortality. Future studies should explore the reason for different sex-specific ceramide profiles and whether ceramides are causally mediating their effects on CVD through CRF.

Effects of Natural Antioxidants on Phospholipid and Ceramide Profiles of 3D-Cultured Skin Fibroblasts Exposed to UVA or UVB Radiation.

Ultraviolet (UV) radiation is one of the primary factors responsible for disturbances in human skin cells phospholipid metabolism. Natural compounds that are commonly used to protect skin, due to their lipophilic or hydrophilic nature, show only a narrow range of cytoprotective activity, which prompts research on their combined application. Therefore, the aim of this study was to examine the effect of ascorbic acid and rutin on the phospholipid and ceramide profiles in UV-irradiated fibroblasts cultured in a three-dimensional system that approximates the culture conditions to the dermis. An ultra-high-performance liquid chromatograph coupled with a quadrupole time-of-flight mass spectrometer was used for phospholipid and ceramide profiling. As a result of UVA and UVB cells irradiation, upregulation of phosphatidylcholines, ceramides, and downregulation of sphingomyelins were observed, while treatment with ascorbic acid and rutin of UVA/UVB-irradiated fibroblast promoted these changes to provide cells a stronger response to stress. Moreover, an upregulation of phosphatidylserines in cells exposed to UVB and treated with both antioxidants suggests the stimulation of UV-damaged cells apoptosis. Our findings provide new insight into action of rutin and ascorbic acid on regulation of phospholipid metabolism, which improves dermis fibroblast membrane properties.