Ceramide Levels Research Articles

Scavenger Receptor BI Deficiency in Mice Is Associated With Plasma Ceramide and Sphingomyelin Accumulation and a Reduced Cholesteryl Ester Fatty Acid Length and Unsaturation Degree.

Scavenger receptor class B type I (SR-BI) is primarily known for its role in the selective uptake of cholesteryl esters (CEs) from high-density lipoproteins (HDLs). Here we investigated whether SR-BI deficiency is associated with other potentially relevant changes in the plasma lipidome than the established effect of HDL-cholesterol elevation. Targeted ultra-high-performance liquid chromatography-tandem mass spectrometry was utilized to measure lipid species in plasma from female wild-type and SR-BI knockout mice. SR-BI deficiency was associated with a reduction in the average CE fatty acid length (-2%; p<0.001) and degree of CE fatty acid unsaturation (-18%; p<0.001) due to a relative shift from longer, polyunsaturated CE species CE (20:4), CE (20:5), and CE (22:6) towards the mono-unsaturated CE (18:1) species. Sphingomyelin (SM) levels were 64% higher (p<0.001) in SR-BI knockout mice without a parallel change in (lyso)phosphatidylcholine (LPC) concentrations, resulting in an increase in the SM/LPC ratio from 0.102±0.005 to 0.163±0.003 (p<0.001). In addition, lower LPC lengths (-5%; p<0.05) and fatty acid unsaturation degrees (-20%; p<0.01) were detected in SR-BI knockout mice. Furthermore, SR-BI deficiency was associated with a 4.7-fold increase (p<0.001) in total plasma ceramide (Cer) levels, with a marked >9-fold rise (p<0.001) in Cer (d18:1/24:1) concentrations. We have shown that SR-BI deficiency in mice not only impacts the CE concentrations, length, and saturation index within the plasma compartment, but is also associated with plasma accumulation of several Cer and SM species that may contribute to the development of specific hematological and metabolic (disease) phenotypes previously detected in SR-BI knockout mice.

Mechanism of Obesity-Related Lipotoxicity and Clinical Perspective.

The link between cellular exposure to fatty acid species and toxicity phenotypes remains poorly understood. However, structural characterization and functional profiling of human plasma free fatty acids (FFAs) analysis has revealed that FFAs are located either in the toxic cluster or in the cluster that is transcriptionally responsive to lipotoxic stress and creates genetic risk factors. Genome-wide short hairpin RNA screen has identified more than 350 genes modulating lipotoxicity. Hypertrophic adipocytes in obese adipose are both unable to expand further to store excess lipids in the diet and are resistant to the antilipolytic action of insulin.In addition to lipolysis, the inability of packaging the excess lipids into lipid droplets causes circulating fatty acids to reach toxic levels in non-adipose tissues. Deleterious effects of accumulated lipid in non-adipose tissues are known as lipotoxicity. Although triglycerides serve a storage function for long-chain non-esterified fatty acid and their products such as ceramide and diacylglycerols (DAGs), overloading of palmitic acid fraction of saturated fatty acids (SFAs) raises ceramide levels. The excess DAG and ceramide load create harmful effects on multiple organs and systems, inducing chronic inflammation in obesity. Thus, lipotoxic inflammation results in β cells death and pancreatic islets dysfunction. Endoplasmic reticulum stress stimuli induce lipolysis by activating cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) and extracellular signal-regulated kinase (Erk) 1/2 signaling in adipocytes. However, palmitic acid-induced endoplasmic reticulum stress-c-Jun N-terminal kinase (JNK)-autophagy axis in hypertrophic adipocytes is a pro-survival mechanism against endoplasmic reticulum stress and cell death induced by SFAs. Endoplasmic reticulum-localized acyl-coenzyme A (CoA): glycerol-3-phosphate acyltransferase (GPAT) enzymes are mediators of lipotoxicity, and inhibiting these enzymes has therapeutic potential for lipotoxicity. Lipotoxicity increases the number of autophagosomes, which engulf palmitic acid, and thus suppress the autophagic turnover. Fatty acid desaturation promotes palmitate detoxification and storages into triglycerides. As therapeutic targets of glucolipotoxicity, in addition to caloric restriction and exercise, there are four different pharmacological approaches, which consist of metformin, glucagon-like peptide 1 (GLP-1) receptor agonists, peroxisome proliferator-activated receptor-gamma (PPARγ) ligands thiazolidinediones, and chaperones are still used in clinical practice. Furthermore, induction of the brown fat-like phenotype with the mixture of eicosapentanoic acid and docosahexaenoic acid appears as a potential therapeutic application for treatment of lipotoxicity.

Mitochondrial electron transport chain, ceramide, and coenzyme Q are linked in a pathway that drives insulin resistance in skeletal muscle.

Insulin resistance (IR) is a complex metabolic disorder that underlies several human diseases, including type 2 diabetes and cardiovascular disease. Despite extensive research, the precise mechanisms underlying IR development remain poorly understood. Previously we showed that deficiency of coenzyme Q (CoQ) is necessary and sufficient for IR in adipocytes and skeletal muscle (Fazakerley et al., 2018). Here, we provide new insights into the mechanistic connections between cellular alterations associated with IR, including increased ceramides, CoQ deficiency, mitochondrial dysfunction, and oxidative stress. We demonstrate that elevated levels of ceramide in the mitochondria of skeletal muscle cells result in CoQ depletion and loss of mitochondrial respiratory chain components, leading to mitochondrial dysfunction and IR. Further, decreasing mitochondrial ceramide levels in vitro and in animal models (mice, C57BL/6J) (under chow and high-fat diet) increased CoQ levels and was protective against IR. CoQ supplementation also rescued ceramide-associated IR. Examination of the mitochondrial proteome from human muscle biopsies revealed a strong correlation between the respirasome system and mitochondrial ceramide as key determinants of insulin sensitivity. Our findings highlight the mitochondrial ceramide-CoQ-respiratory chain nexus as a potential foundation of an IR pathway that may also play a critical role in other conditions associated with ceramide accumulation and mitochondrial dysfunction, such as heart failure, cancer, and aging. These insights may have important clinical implications for the development of novel therapeutic strategies for the treatment of IR and related metabolic disorders.

Mitochondrial electron transport chain, ceramide, and coenzyme Q are linked in a pathway that drives insulin resistance in skeletal muscle

Insulin resistance (IR) is a complex metabolic disorder that underlies several human diseases, including type 2 diabetes and cardiovascular disease. Despite extensive research, the precise mechanisms underlying IR development remain poorly understood. Previously we showed that deficiency of coenzyme Q (CoQ) is necessary and sufficient for IR in adipocytes and skeletal muscle (Fazakerley et al., 2018). Here, we provide new insights into the mechanistic connections between cellular alterations associated with IR, including increased ceramides, CoQ deficiency, mitochondrial dysfunction, and oxidative stress. We demonstrate that elevated levels of ceramide in the mitochondria of skeletal muscle cells result in CoQ depletion and loss of mitochondrial respiratory chain components, leading to mitochondrial dysfunction and IR. Further, decreasing mitochondrial ceramide levels in vitro and in animal models (mice, C57BL/6J) (under chow and high-fat diet) increased CoQ levels and was protective against IR. CoQ supplementation also rescued ceramide-associated IR. Examination of the mitochondrial proteome from human muscle biopsies revealed a strong correlation between the respirasome system and mitochondrial ceramide as key determinants of insulin sensitivity. Our findings highlight the mitochondrial ceramide–CoQ–respiratory chain nexus as a potential foundation of an IR pathway that may also play a critical role in other conditions associated with ceramide accumulation and mitochondrial dysfunction, such as heart failure, cancer, and aging. These insights may have important clinical implications for the development of novel therapeutic strategies for the treatment of IR and related metabolic disorders.

Desipramine ameliorates fine particulate matter-induced hepatic insulin resistance by modulating the ceramide metabolism in mice

Recent research has highlighted a correlation between exposure to ambient fine particulate matter (PM2.5) and the development of systemic insulin resistance (IR) along with an elevated risk of diabetes. Ceramide has emerged as one of the pathogenic mechanisms contributing to IR. The inhibition of acid sphingomyelinase (ASMase) activity by desipramine (DES) has been shown to effectively reduce ceramide levels. In the present study, 24 female C57BL/6 N mice were randomized into one of the four groups: the filtered air exposure (FA) group, the concentrated PM2.5 exposure (PM) group, the concentrated PM2.5 treated with low-dose DES (DL) group, and the concentrated PM2.5 treated with high-dose DES (DH) group. The PM, DL and DH groups were exposed to PM2.5 for an 8-week period within a whole-body exposure system. The study encompassed extensive examinations of glucose homeostasis, liver lipid profile, ceramide pathway, and insulin signaling pathway. Our results demonstrated that PM2.5 exposure caused impaired glucose tolerance, elevated ceramide levels, increased phosphorylation PP2A, reduced Akt phosphorylation, and hindered GLUT2 expression. Remarkably, DES administration mitigated PM2.5-induced IR by effectively lowering ceramide levels. In conclusion, the reduction of ceramide levels by DES may be a promising therapeutic strategy for coping PM2.5-induced IR.

Astaxanthin Ameliorates Worsened Muscle Dysfunction of MDX Mice Fed with a High-Fat Diet through Reducing Lipotoxicity and Regulating Gut Microbiota.

Duchenne muscular dystrophy (DMD), a severe X-linked inherited neuromuscular disease, has a high prevalence of obesity. Obesity exacerbates muscle damage and results in adverse clinical outcomes. Preventing obesity helps DMD patients delay disease progression and improve quality of life. Astaxanthin (AX) is a kind of carotenoid which has antioxidant and anti-adipogenesis effects. In this study, male C57BL/10ScSnDmdmdx/J mice were fed with a normal diet, a high-fat diet (HFD), and an HFD containing AX for 16 weeks, respectively. The results showed that AX significantly increased gastrocnemius fiber cross-section area and grip strength, improved treadmill endurance test and mitochondrial morphology, and reduced muscle triglyceride and malonaldehyde levels compared to the HFD. Lipidomic analysis revealed that AX decreased high levels of triglyceride, diglyceride, ceramides, and wax ester induced by HFD. Gut microbiota analysis indicated that AX supplementation failed to alleviate abnormal microbiota diversity, but increased the relative abundances of Akkermansia, Bifidobacterium, Butyricicoccus, and Staphylococcus. In conclusion, AX was expected to alleviate disease progression associated with obesity in DMD patients by reducing lipotoxicity and increasing the abundance of beneficial bacteria.

Ceramide enhanced the hepatic glucagon response through regulation of CREB activity

Background & aimsHyperglycemia is associated with lipid disorders in patients with diabetes. Ceramides are metabolites involved in sphingolipid metabolism that accumulate during lipid disorders and exert deleterious effects on glucose and lipid metabolism. However, the effects of ceramide on glucagon-mediated hepatic gluconeogenesis remain largely unknown. This study was designed to investigate the impact of ceramides on gluconeogenesis in the context of the hepatic glucagon response, with the aim of finding new pharmacological interventions for hyperglycemia in diabetes. MethodsLiquid chromatography-mass spectrometry was used to quantify ceramide content in the serum of patients with diabetes. Primary hepatocytes were isolated from male C57BL/6J mice to study the effects of ceramide on hepatic glucose production. Immunofluorescence staining was performed to view cAMP-responsive element-binding protein (CREB)- regulated transcription co-activator 2 (CRTC2) nuclear translocation in hepatocytes. Serine palmitoyl-transferase, long chain base subunit 2 (Sptlc2) knockdown mice were generated using an adeno-associated virus containing shRNA, and hepatic glucose production was assessed glucagon tolerance and pyruvate tolerance tests in mice fed a normal chow diet and high-fat diet. ResultsIncreased ceramide levels were observed in the serum of patients newly diagnosed with type 2 diabetes. De novo ceramide synthesis was activated in mice with metabolic disorders. Ceramide enhanced hepatic glucose production in primary hepatocytes. In contrast, genetic silencing of Sptlc2 prevented this process. Mechanistically, ceramides de-phosphorylate CRTC2 (Ser 171) and facilitate its translocation into the nucleus for CREB activation, thereby augmenting the hepatic glucagon response. Hepatic Sptlc2 silencing blocked ceramide generation in the liver and thus restrained the hepatic glucagon response in mice fed a normal chow diet and high-fat diet. ConclusionsThese data indicate that ceramide serves as an intracellular messenger that augments hepatic glucose production by regulating CRTC2/CREB activity in the context of the hepatic glucagon response, suggesting that CRTC2 phosphorylation might be a potential node for pharmacological interventions to restrain the hyperglycemic response during fasting in diabetes.

Comparison of skin barrier abnormalities and epidermal ceramide profiles among three ω-O-acylceramide synthesis-deficient mouse strains

BackgroundThe epidermis contains many structurally diverse ceramides, which form the skin permeability barrier (skin barrier). Mutations in genes involved in the synthesis of ω-O-acylceramides (acylceramides) and protein-bound ceramides cause ichthyosis. ObjectiveWe aimed to elucidate the relationship between the degree of skin barrier impairment and changes in epidermal ceramide profiles caused by mutations in acylceramide synthesis genes. MethodsKnockout (KO) mice of three genes—fatty acid (FA) ω-hydroxylase Cyp4f39 (human CYP4F22 ortholog), FA elongase Elovl1, and acyl-CoA synthetase Fatp4—were subjected to transepidermal water loss measurement, toluidine blue staining, and epidermal ceramide profiling via liquid chromatography coupled with tandem mass spectrometry. ResultsTransepidermal water loss was highest in Cyp4f39 KO mice, followed by Elovl1 KO and Fatp4 KO mice, and Cyp4f39 KO mice also showed the strongest degree of toluidine blue staining. In Cyp4f39 KO, Elovl1 KO, and Fatp4 KO mice, acylceramide levels were 0.6%, 1.6%, and 12%, respectively, of those in wild-type mice. Protein-bound ceramide levels were 0.2%, 30%, and 33%, respectively, of those in wild-type mice. We also observed a near-complete absence of ω-hydroxy ceramides in Cyp4f39 KO mice, reduced total ceramide levels and shortened FA moieties in Elovl1 KO mice, and increased hydroxylated ceramide levels and slightly shortened FA moieties in Fatp4 KO mice. ConclusionsThe degree of reduction in protein-bound ceramide levels is probably related to the severity of skin barrier defects in these three strains. However, reduced acylceramide levels and other changes in ceramide composition unique to each KO strain are also involved.

Overexpression of ORMDL3 confers sexual dimorphism in diet-induced non-alcoholic steatohepatitis

ObjectiveThe bioactive sphingolipid metabolites ceramide and sphingosine-1-phosphate (S1P) accumulate with overnutrition and have been implicated in non-alcoholic steatohepatitis (NASH) development. ORMDL3, a negative regulator of the rate-limiting step in ceramide biosynthesis, has been identified as an obesity-related gene. Therefore, we assessed the role of ORMDL3 in diet-induced obesity and development of NASH. MethodsGlobally overexpressing Ormdl3-Flag transgenic mice (ORMDL3TG) were fed a western high-fat, carbohydrate and cholesterol enriched diet, with high fructose-glucose drinking water. Physiological, biochemical and sphingolipidomic analyses were employed to measure the effect of ORMDL3 overexpression on NASH development. ResultsORMDL3TG male but not female mice fed a western high-fat diet and sugar water had exacerbated adipocyte hypertrophy together with increased severity of white adipose inflammation and fibrosis. Hepatic steatosis, dyslipidemia, impaired glucose homeostasis, hyperinsulinemia, and insulin resistance were significantly more severe only in obese ORMDL3TG male mice that accompanied dramatic liver fibrosis, inflammation, and formation of hepatic crown-like structures, which are unique features of human and murine NASH. Obesogenic diet induces ORMDL expression in male mice but reduces it in females. Mechanistically, overexpression of Ormdl3 lowered the levels of S1P and ceramides only in obese female mice and antithetically increased them in tissues of obese males. ORMDL3TG male mice exhibited a much greater induction of the UPR, propagating ER stress that contributed to their early development of NASH. ConclusionsThis study uncovered a previously unrecognized role for ORMDL3 in sexual dimorphism important for the development and progression of NASH.

The Novel Ceramide- and Phosphatidylcholine-Based Risk Score for the Prediction of New-Onset of Hypertension.

Ceramides and other sphingolipids are implicated in vascular dysfunction and inflammation. They have been suggested as potential biomarkers for hypertension. However, their specific association with hypertension prevalence and onset requires further investigation. This study aimed to identify specific ceramide and phosphatidylcholine species associated with hypertension prevalence and onset. The 2002 FINRISK (Finnish non-communicable risk factor survey) study investigated the association between coronary event risk scores (CERT1 and CERT2) and hypertension using prevalent and new-onset hypertension groups, both consisting of 7722 participants, over a span of 10 years. Ceramide and phosphatidylcholine levels were measured using tandem liquid chromatography-mass spectrometry. Ceramide and phosphatidylcholine ratios, including ceramide (d18:1/18:0), ceramide (d18:1/24:1), phosphatidylcholine (16:0/16:0), and the ratio of ceramide (d18:1/18:0)/(d18:1/16:0), are consistently associated with both prevalence and new-onset hypertension. Ceramide (d18:1/24:0) was also linked to both hypertension measures. Adjusting for covariates, CERT1 and CERT2 showed no-longer-significant associations with hypertension prevalence, but only CERT2 predicted new-onset hypertension. Plasma ceramides and phosphatidylcholines are crucial biomarkers for hypertension, with imbalances potentially contributing to its development. Further research is needed to understand the underlying mechanisms by which ceramides will contribute to the development of hypertension.

Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in an Alzheimer’s disease mouse model

BackgroundCognitive decline in Alzheimer’s disease (AD) is associated with hyperphosphorylated tau (pTau) propagation between neurons along synaptically connected networks, in part via extracellular vesicles (EVs). EV biogenesis is triggered by ceramide enrichment at the plasma membrane from neutral sphingomyelinase2 (nSMase2)-mediated cleavage of sphingomyelin. We report, for the first time, that human tau expression elevates brain ceramides and nSMase2 activity.MethodsTo determine the therapeutic benefit of inhibiting this elevation, we evaluated PDDC, the first potent, selective, orally bioavailable, and brain-penetrable nSMase2 inhibitor in the transgenic PS19 AD mouse model. Additionally, we directly evaluated the effect of PDDC on tau propagation in a mouse model where an adeno-associated virus (AAV) encoding P301L/S320F double mutant human tau was stereotaxically-injected unilaterally into the hippocampus. The contralateral transfer of the double mutant human tau to the dentate gyrus was monitored. We examined ceramide levels, histopathological changes, and pTau content within EVs isolated from the mouse plasma.ResultsSimilar to human AD, the PS19 mice exhibited increased brain ceramide levels and nSMase2 activity; both were completely normalized by PDDC treatment. The PS19 mice also exhibited elevated tau immunostaining, thinning of hippocampal neuronal cell layers, increased mossy fiber synaptophysin immunostaining, and glial activation, all of which were pathologic features of human AD. PDDC treatment reduced these changes. The plasma of PDDC-treated PS19 mice had reduced levels of neuronal- and microglial-derived EVs, the former carrying lower pTau levels, compared to untreated mice. In the tau propagation model, PDDC normalized the tau-induced increase in brain ceramides and significantly reduced the amount of tau propagation to the contralateral side.ConclusionsPDDC is a first-in-class therapeutic candidate that normalizes elevated brain ceramides and nSMase2 activity, leading to the slowing of tau spread in AD mice.

Correlational analysis of plasma metabolome and brain imaging in a humanized APOE mouse model

AbstractBackgroundApolipoprotein E (APOE) ε4 is the strongest genetic risk factor for the development of late‐onset Alzheimer’s disease (LOAD). Additionally, females have a 2x greater risk of developing LOAD than males. LOAD patients show brain glucose hypometabolism and severe reduction in hippocampal volume. Hippocampal atrophy has also been linked with plasma ceramide and phosphotidylcholine (PC) levels in these patients. This study explores the effects of sex and genotype on the plasma metabolome and potential correlations to brain imaging metrics in an aged humanized APOE (hAPOE) mouse model.MethodPlasma samples from 23–25‐month‐old hAPOE mice (37M/32F) expressing ε3/3, ε3/4 or ε4/4 genotypes were analyzed via mass spectrometry using the Biocrates MxP® Quant 500 platform. In a subset of these animals (24M/20F), in‐vivo FDG‐PET and high‐resolution ex‐vivo MRI were obtained. Cerebral FDG‐PET standardized uptake values were normalized to cerebellum (SUVr). Cerebral SUVr and regional volumes were correlated with detected metabolites and metabolic indicators using Pearson correlations. Two‐way ANOVAs were used to identify sex and genotype effects with post‐hoc t‐tests to determine statistical significance.ResulthAPOE ε3/3 mice had significantly greater cholesteryl ester (54%; p &lt; 0.026) and lysophosphotidylcholine (lysoPC; 27%; p &lt; 0.031) levels compared to ε4/4 mice. Females had lower levels of PCs (93%; p &lt; 0.007), lysoPCs (82%; p &lt; 0.018), triglycerides (62%; p &lt; 0.045), and 1‐Met‐His (p = 5.84E‐25) than males. Significant positive correlations were observed between cerebral SUVr and PCs (45%; p &lt; 0.049) as well as lysoPCs (82%; p &lt;0.017). Total brain volume was negatively correlated with plasma 3‐Met‐His:creatinine ratio, indicative of muscle protein degradation (r = ‐0.44; p = 0.003) and positively correlated with (LysoPC+ arachidonic acid): PC ratio, indicative of phospholipase A2 activity (r = 0.42; p = 0.004). Right hippocampal volume percentage was significantly positively correlated with PCs (64%; p &lt; 0.045) and 1‐Met‐His (p = 0.00067).ConclusionAt a comparable human age of ∼ 70 years, within the humanized APOE mouse, sex was the major contributing factor to metabolic differences in peripheral blood plasma. Levels of peripheral metabolites correlated with brain volumetrics and glucose metabolism, highlighting potential therapeutic targets for interventions designed to preserve neuronal health in AD.

Chronic nSMase2 Inhibition Suppresses Neuronal Exosome Spreading In Vivo &amp; Induces Sex‐Specific Attenuation of AD Pathology in APPNL‐F/NL‐F Knock‐In Mice

AbstractBackgroundAltered ceramide metabolism is implicated in Alzheimer’s disease (AD) progression. Although prior work shows that inhibition of neutral sphingomyelinase (nSMase) 2, a key enzyme responsible for hydrolysis of sphingomyelin to ceramide, reduces exosome secretion, attenuates Aβ pathology, and improves cognitive function, these studies have been limited to in vitro application or short‐term treatments in fast‐progressing models.MethodWe employed the slow‐progressing APPNL‐F/NL‐F knock‐in (APP KI) AD mouse model and cell type‐specific exosome reporter CD63‐GFPf/f mice to investigate the impact of chronic long‐term nSmase2 inhibition on in vivo neuron‐derived exosome dynamics, region‐specific Aβ plaque load, and cognitive function. Male and female APPNL‐F/NL‐F‐CD63‐GFPf/+ (APP KI‐CD63) mice were treated daily with the nSmase2 inhibitor, GW4869 (GW; 1.25mg/kg BW; i.p.), or vehicle (VEH, DMSO in saline), from 8 months old (mo.) to 13mo. and from 10 mo. to 18mo. We also analyzed ceramide levels in both APP KI and WT mice. Brain‐derived exosomes of 14mo. APP KI females versus males and age‐ and sex‐matched WT mice were also isolated and quantified.ResultWe found significant elevations in multiple ceramide species from somatosensory cortex (SC) samples of 14mo. APP KI mice compared to age‐ and sex‐matched WT controls. We also found a sex‐specific increase in total exosomes in 14mo. APP KI females versus males that was absent in WT mice. Chronic inhibition of nSMase2 by GW4869 leads to significantly suppression of neuronal exosome spreading. Non‐linear regression analyses of size distribution curves showed consistent shifts to smaller plaque sizes in GW‐treated APP KI females, which were accompanied by decreased plaque numbers in each region examined. Conversely, plaque load was largely unaffected by GW treatment in APP KI males. T maze trials to examine spatial working memory revealed a female‐specific reduction in spontaneous alternation rate in APP KI vs. WT mice, which was significantly reversed with GW treatment.ConclusionOur results demonstrate that chronic nSMase2 inhibition suppresses neuronal exosome spreading in APPNL‐F/NL‐F knock‐in mice and preferentially attenuates Aβ pathology and cognitive dysfunction in females, pointing to a strong contribution of sex‐specific alterations in ceramide metabolism and exosome dynamics to the progression of AD‐like pathology in this model.

Targeting ABCA12-controlled ceramide homeostasis inhibits breast cancer stem cell function and chemoresistance.

Cancer stem cells (CSCs) drive tumor growth, metastasis, and chemoresistance. While emerging evidence suggests that CSCs have a unique dependency on lipid metabolism, the functions and regulation of distinct lipid species in CSCs remain poorly understood. Here, we developed a stem cell factor SOX9-based reporter for isolating CSCs in primary tumors and metastases of spontaneous mammary tumor models. Transcriptomic analyses uncover that SOX9high CSCs up-regulate the ABCA12 lipid transporter. ABCA12 down-regulation impairs cancer stemness and chemoresistance. Lipidomic analyses reveal that ABCA12 maintains cancer stemness and chemoresistance by reducing intracellular ceramide abundance, identifying a CSC-associated function of ABCA subfamily transporter. Ceramide suppresses cancer stemness by inhibiting the YAP-SOX9 signaling pathway in CSCs. Increasing ceramide levels in tumors enhances their sensitivity to chemotherapy and prevents the enrichment of SOX9high CSCs. In addition, SOX9high and ABCA12high cancer cells contribute to chemoresistance in human patient-derived xenografts. These findings identify a CSC-suppressing lipid metabolism pathway that can be exploited to inhibit CSCs and overcome chemoresistance.

Skin Barrier Function: The Interplay of Physical, Chemical, and Immunologic Properties.

An intact barrier function of the skin is important in maintaining skin health. The regulation of the skin barrier depends on a multitude of molecular and immunological signaling pathways. By examining the regulation of a healthy skin barrier, including maintenance of the acid mantle and appropriate levels of ceramides, dermatologists can better formulate solutions to address issues that are related to a disrupted skin barrier. Conversely, by understanding specific skin barrier disruptions that are associated with specific conditions, such as atopic dermatitis or psoriasis, the development of new compounds could target signaling pathways to provide more effective relief for patients. We aim to review key factors mediating skin barrier regulation and inflammation, including skin acidity, interleukins, nuclear factor kappa B, and sirtuin 3. Furthermore, we will discuss current and emerging treatment options for skin barrier conditions.

Sphingolipid classes and the interrelationship with pediatric asthma and asthma risk factors.

While dysregulated sphingolipid metabolism has been associated with risk of childhood asthma, the specific sphingolipid classes and/or mechanisms driving this relationship remain unclear. We aimed to understand the multifaceted role between sphingolipids and other established asthma risk factors that complicate this relationship. We performed targeted LC-MS/MS-based quantification of 77 sphingolipids in plasma from 997 children aged 6 years from two independent cohorts (VDAART and COPSAC2010 ). We examined associations of circulatory sphingolipids with childhood asthma, lung function, and three asthma risk factors: functional SNPs in ORMDL3, low vitamin D levels, and reduced gut microbial maturity. Given racial differences between these cohorts, association analyses were performed separately and then meta-analyzed together. We observed elevations in circulatory sphingolipids with asthma phenotypes and risk factors; however, there were differential associations of sphingolipid classes with clinical outcomes and/or risk factors. While elevations from metabolites involved in ceramide recycling and catabolic pathways were associated with asthma and worse lung function [meta p-value range: 1.863E-04 to 2.24E-3], increased ceramide levels were associated with asthma risk factors [meta p-value range: 7.75E-5 to .013], but not asthma. Further investigation identified that some ceramides acted as mediators while some interacted with risk factors in the associations with asthma outcomes. This study demonstrates the differential role that sphingolipid subclasses may play in asthma and its risk factors. While overall elevations in sphingolipids appeared to be deleterious overall; elevations in ceramides were uniquely associated with increases in asthma risk factors only; while elevations in asthma phenotypes were associated with recycling sphingolipids. Modification of asthma risk factors may play an important role in regulating sphingolipid homeostasis via ceramides to affect asthma. Further function work may validate the observed associations.

Recurrent de novo SPTLC2 variant causes childhood-onset amyotrophic lateral sclerosis (ALS) by excess sphingolipid synthesis

BackgroundAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the upper and lower motor neurons with varying ages of onset, progression and pathomechanisms. Monogenic childhood-onset ALS, although rare, forms an...

The role of BCL2L13 in glioblastoma: turning a need into a target.

Glioblastoma (GBM) is the most common aggressive central nervous system cancer. GBM has a high mortality rate, with a median survival time of 12-15 months after diagnosis. A poor prognosis and a shorter life expectancy may result from resistance to standard treatments such as radiation and chemotherapy. Temozolomide has been the mainstay treatment for GBM, but unfortunately, there are high rates of resistance with GBM bypassing apoptosis. A proposed mechanism for bypassing apoptosis is decreased ceramide levels, and previous research has shown that within GBM cells, B cell lymphoma 2-like 13 (BCL2L13) can inhibit ceramide synthase. This review aims to discuss the causes of resistance in GBM cells, followed by a brief description of BCL2L13 and an explanation of its mechanism of action. Further, lipids, specifically ceramide, will be discussed concerning cancer and GBM cells, focusing on ceramide synthase and its role in developing GBM. By gathering all current information on BCL2L13 and ceramide synthase, this review seeks to enable an understanding of these pieces of GBM in the hope of finding an effective treatment for this disease.

Glucagon-like peptide-1 receptor agonist regulates fat browning by altering the gut microbiota and ceramide metabolism.

Studies have shown that antidiabetic drugs can alter the gut microbiota. The hypoglycemic effects of the drugs can be attributed in part to certain species in the gut microbiome that help the drugs work more effectively. In addition, increasing energy expenditure via the induction of adipose tissue browning has become an appealing strategy to treat obesity and associated metabolic complications. Currently, glucagon-like peptide-1 receptor agonist (GLP-1 RA) treatment for metabolic disorders such as obesity and type 2 diabetes has been widely studied. To determine the mechanism of a long-acting GLP-1 RA affects adipose tissue browning and the gut microbiome, we treated high-fat diet mice with GLP-1 RA and demonstrated that the drug can regulate adipose tissue browning. 16S rRNA and untargeted metabolomics assays suggested that it increased the abundance of bacterium Lactobacillus reuteri and decreased serum ceramide levels in mice. L. reuteri was negatively correlated with ceramide. We found that the mechanism of ceramide decline was alkaline ceramidase 2 (Acer2) overexpression. Moreover, L. reuteri can play a therapeutic synergistic role with GLP-1 RA, suggesting that gut microbiota can be used as a part of the treatment of diabetes.

Specialized Retinal Endothelial Cells Modulate Blood-Retina Barrier in Diabetic Retinopathy.

Endothelial cells (EC) play essential roles in retinal vascular homeostasis. This study aimed to characterize retinal EC heterogeneity and functional diversity using single-cell RNA sequencing. Systematic analysis of cellular compositions and cell-cell interaction networks identified a unique EC cluster with high inflammatory gene expression in diabetic retina; sphingolipid metabolism is a prominent aspect correlated with changes in retinal function. Among sphingolipid-related genes, alkaline ceramidase 2 (ACER2) showed the most significant increase. Plasma samples of patients with non-proliferative diabetic retinopathy (NPDR) with or without diabetic macular edema (DME) and active PDR were collected for mass spectrometry analysis. Metabolomic profiling revealed that the ceramide levels were significantly elevated in NPDR-NDME/DME and further increased in active PDR compared with control patients. In vitro analyses showed that ACER2 overexpression retarded endothelial barrier breakdown induced by ceramide, while silencing of ACER2 further disrupted the injury. Moreover, intravitreal injection of the recombinant ACER2 adeno-associated virus rescued diabetes-induced vessel leakiness, inflammatory response, and neurovascular disease in diabetic mouse models. Together, this study revealed a new diabetes-specific retinal EC population and a negative feedback regulation pathway that reduces ceramide content and endothelial dysfunction by upregulating ACER2 expression. These findings provide insights into cell-type targeted interventions for diabetic retinopathy.