Cardiometabolic diseases-including Type 2 diabetes and obesity-remain leading causes of global mortality. Recent advancements in metabolomics have facilitated the identification of metabolites that are integral to the development of insulin resistance, a characteristic feature of cardiometabolic disease. Key metabolites, such as branched-chain amino acids (BCAAs), ceramides, glycine, and glutamine, have emerged as valuable biomarkers for early diagnosis, risk stratification, and potential therapeutic targets. Elevated BCAAs and ceramides are strongly associated with insulin resistance and Type 2 diabetes, whereas glycine exhibits an inverse relationship with insulin resistance, making it a promising therapeutic target. Metabolites involved in energy stress, including ketone bodies, lactate, and nicotinamide adenine dinucleotide (NAD⁺), regulate insulin sensitivity and metabolic health, with ketogenic diets and NAD⁺ precursor supplementation showing potential benefits. Additionally, the novel biomarker N-lactoyl-phenylalanine further underscores the complexity of metabolic regulation and its therapeutic potential. This review underscores the potential of metabolite-based diagnostics and precision medicine, which could enhance efforts in the prevention, diagnosis, and treatment of cardiometabolic diseases, ultimately improving patient outcomes and quality of life.

We aimed to evaluate the associations of hexosylceramides (HexCers) and their ratio with incident type 2 diabetes mellitus (T2DM) and explore underlying mechanisms.

We conducted a nested case-control study using the Suzhou chronic disease cohort including 234 T2DM cases and 468 controls, 1:2 matched on age (±2 y) and sex. HexCer(d18:1/16:1) and HexCer(d18:1/24:1) were measured by targeted UPLC-MS/MS. Multivariable conditional logistic regression was used to estimate the associations of these HexCer species and their ratio with T2DM risk.

After adjustment for potential confounders, compared with the lowest quartile, the highest quartile of HexCer(d18:1/24:1) was positively associated with T2DM risk (OR: 1.91; 95%CI, 1.12, 3.26; P-trend <0.05). The ratio of HexCer(d18:1/24:1) to HexCer(d18:1/16:1) showed a positive association with T2DM risk (OR: 1.89; 95%CI, 1.13, 3.18; P-trend <0.05). On the natural log scale, each SD increases in HexCer(d18:1/24:1) and its ratio to HexCer(d18:1/16:1) increased by 29% and 30%, respectively. No significant association for HexCer(d18:1/16:1) was found. Additive value of HexCer(d18:1/24:1) or HexCer(d18:1/24:1)/HexCer(d18:1/16:1) ratio for prediction of T2DM above traditional risk factors.

HexCer(d18:1/24:1) and its ratio to HexCer(d18:1/16:1) are positively associated with incident T2DM in a community-based Chinese population. Future studies are warranted to confirm our findings.

Lipid profiles change in human immunodeficiency virus (HIV) infection and correlate with inflammation. Lipidomic alterations are impacted by multiple non-HIV-related behavioral risk factors; thus, use of animal models in which these behavioral factors are controlled may inform on the specific lipid changes induced by simian immunodeficiency virus (SIV) infection and/or antiretroviral therapy (ART).

Using ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy, we assessed and compared (ANOVA) longitudinal lipid changes in naïve and ART-treated SIV-infected pigtailed macaques (PTMs). Key parameters of infection (IL-6, TNFa, D-dimer, CRP and CD4+ T cell counts) were correlated (Spearman) with lipid concentrations at critical time points of infection and treatment.

Sphingomyelins (SM) and lactosylceramides (LCER) increased during acute infection, returning to baseline during chronic infection; Hexosylceramides (HCER) increased throughout infection, being normalized with prolonged ART; Phosphatidylinositols (PI) and lysophosphatidylcholines (LPC) decreased with SIV infection and did not return to normal with ART; Phosphatidylethanolamines (PE), lysophosphatidylethanolamines (LPE) and phosphatidylcholines (PC) were unchanged by SIV infection, yet significantly decreased throughout ART. Specific lipid species (SLS) were also substantially modified by SIV and/or ART in most lipid classes. In conclusion, using a metabolically controlled model, we identified specific lipidomics signatures of SIV infection and/or ART, some of which were similar to people living with HIV (PWH). Many SLS were identical to those involved in development of organ dysfunctions encountered in virally suppressed individuals. Lipid changes also correlated with markers of disease progression, inflammation and coagulation.

Our data suggest that lipidomic profile alterations contribute to residual systemic inflammation and comorbidities seen in HIV/SIV infections and therefore may be used as biomarkers of SIV/HIV comorbidities. Further exploration into the benefits of interventions targeting dyslipidemia is needed for the prevention HIV-related comorbidities.

Lipids are a complex entity of different molecules, among which ceramides (Cers), ubiquitous sphingolipids with remarkable biological activity, can represent a potential additive biomarker that can be used to better understand the underlying mechanisms which drive the onset and development of atherosclerotic damage and plaque vulnerability and facilitate coronary disease management, as possible risk/prognostic biomarkers and targets for therapeutic intervention. Accordingly, this review aims to discuss the available results on the role Cersplay in contributing to atherosclerosis development and acute coronary event precipitation, their impact on complications and adverse prognosis, as well as the impact of treatment options in modulating Cerlevels.

Cognitive decline and late-onset dementia pose significant challenges in aging societies, and many dementia cases could be prevented or delayed through modification of associated risk factors, many of which are tied to cardiovascular and metabolic dysfunction. As individuals age, the blood-brain barrier becomes more permeable, easing the exchange of molecules between the bloodstream and the brain. Consequently, blood-based biological markers (so-called biomarkers) provide a minimally invasive and accessible means of accessing molecular changes associated with aging and neurodegeneration.

Circulating free fatty acids, also called nonesterified fatty acids (NEFAs), and sphingolipids are associated with cardiovascular disease, insulin resistance, and diabetes; thus, could be promising candidates as biomarkers for cognitive decline and dementia.

The opportunity to study such minimally invasive biomarkers further opens up potential new avenues for improved understanding of the underlying biology of diseases of the brain.

Lipid species are emerging as biomarkers for cardiometabolic risk in both adults and children. The genetic regulation of lipid species and their impact on cardiometabolic risk during early life remain unexplored.

Using mass spectrometry-based lipidomics, we measured 227 plasma lipid species in 1149 children and adolescents (44.8% boys) with a median age of 11.2 years. We performed genome-wide association analyses to identify genetic variants influencing lipid species. Colocalisation and Mendelian randomisation (MR) analyses were performed to infer causality between lipid species and cardiometabolic outcomes.

We identified 37 genome-wide significant loci for 52 lipid species, nine of which are previously unreported. Colocalisation analyses revealed that seven lipid loci shared genetic variants associated with adult cardiometabolic outcomes. One-sample MR analysis identified positive causal associations between ceramides and liver enzymes, sphingomyelins and hemoglobin A1c (HbA1c), and phosphatidylethanolamines and high-sensitivity C-reactive protein in children and adolescents. Two-sample MR using adult-based summary statistics showed consistent direction of associations and indicated additional causal links, specifically between ceramides and elevated HbA1c levels, and phosphatidylinositols with elevated liver enzymes.

These findings highlight the potential long-term implications of plasma lipid genetic determinants on cardiometabolic risk.

Novo Nordisk Foundation, The Innovation Fund Denmark, The Danish Heart Foundation, EU Horizon, and LundbeckFonden.

The effects of usual physical activity on physiology and disease prevention are not fully understood. We examined the associations between physical activity, metabolites, and breast cancer risk.

Physical activity levels were assessed using doubly labeled water, accelerometers, and 24-hour recalls in the Interactive Diet and Activity Tracking in AARP (IDATA) Study (N = 707 participants, ages 50-74 years, 51% women), with 1 to 6 assessments over 12 months and 2 blood sample collections. Partial Spearman correlations were used to estimate associations between physical activity and 843 serum metabolites, corrected for multiple testing. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of metabolites with postmenopausal breast cancer in a nested case-control study (621 cases, 621 controls); all statistical tests were 2-sided.

Physical activity was associated with 164 metabolites spanning numerous pathways, including amino acid and fatty acid metabolism. Twelve of these metabolites were also associated with breast cancer risk, 10 of which supported a protective role of physical activity. Notably, higher physical activity was associated with lower 16alpha-hydroxy dehydroepiandrosterone 3-sulfate (sulfated steroid) and adipoylcarnitine (fatty acid), both of which were associated with increased breast cancer risk (OR per 1 standard deviation [SD] = 1.34, 95% CI = 1.16 to 1.55 and 1.26, 1.11 to 1.42, respectively). Higher physical activity energy expenditure was also associated with lower sphingomyelin (d18:1/20:1, d18:2/20:0), which was associated with a reduced breast cancer risk (OR = 0.82, 95% CI = 0.73 to 0.93).

Physical activity is associated with a broad range of metabolites, many of which are consistent with a protective effect against breast cancer. Our findings highlight potential metabolic pathways for cancer prevention.

 Ceramides are lipid species that play several physiological roles in the body, including stress response, inflammation, and apoptosis, and their involvement in lipid metabolism and energy production makes them crucial in the pathophysiology of heart failure (HF).

 Several species of ceramides and ceramide signatures have recently been investigated as possible biomarkers of cardiovascular disease (CVD), and risk scores have demonstrated prognostic value in stratifying patients by risk and possibly predicting adverse cardiac events. With growing interest in targeting metabolic dysfunction, understanding the role of ceramides in CVD also opens the possibility of novel therapeutics that target ceramide metabolism to improve cardiac function and cardiac outcomes in patients.  Understanding the role of ceramides in CVD opens the possibility of novel diagnostics and theragnostic targeting ceramide metabolism to improve cardiac function and cardiac outcomes in patients with heart failure.

Inhibition of the ceramide synthetic pathway with myriocin or an antisense oligonucleotide (ASO) targeting dihydroceramide desaturase (DES1) both improved hepatic insulin sensitivity in rats fed either a saturated or unsaturated fat diet and was associated with reductions in both hepatic ceramide and plasma membrane (PM)-sn-1,2-diacylglycerol (DAG) content. The insulin sensitizing effects of myriocin and Des1 ASO were abrogated by acute treatment with an ASO against DGAT2, which increased hepatic PM-sn-1,2-DAG but not hepatic C16 ceramide content. Increased PM-sn-1,2-DAG content was associated with protein kinase C (PKC)ε activation, increased insulin receptor (INSR)T1150 phosphorylation leading to reduced insulin-stimulated INSRY1152/AktS473 phosphorylation, and impaired insulin-mediated suppression of endogenous glucose production. These results demonstrate that inhibition of de novo ceramide synthesis by either myriocin treatment or DES1 knockdown protects against lipid-induced hepatic insulin resistance through a C16 ceramide-independent mechanism and that they mediate their effects to protect from lipid-induced hepatic insulin resistance via the PM-sn-1,2-DAG-PKCε-INSRT1150 phosphorylation pathway.

Aim: We hypothesized that milk, yogurt, and cheese have differential impacts on energy expenditure (EE) and obesity in mice fed a high-fat diet (HFD). Methods: C57BL/6 mice (n = 16 per group) were fed a HFD or a HFD supplemented with fat-free milk (MILK), fat-free plain yogurt (YOG), or reduced-fat cheddar cheese (CHE; 19 kcal% fat), each provided at 10% of the daily energy intake, for 8 weeks. EE was quantified using a metabolic chamber. Metabolic pathways related to BAT mitochondrial function and uncoupling protein 1 (UCP1) abundance were assessed. Serum lipidomic profiles were analyzed to identify potential mediators of the observed effects. Results: MILK supplementation lowered weight gain and fat accumulation and enhanced EE and BAT thermogenesis, perhaps via the SIRT1-AMPK-PGC1α axis in BAT. This led to elevated UCP1 abundance and enhanced the abundance of hormone-sensitive lipase (HSL). MILK also altered serum lipid species, indicating enhanced energy use, and promoted BAT thermogenesis and mitochondrial function pathways. YOG exhibited a similar pattern but a lower magnitude of effects than MILK on reducing weight gain and fat mass, increasing EE, and BAT thermogenic proteins, including AMPK-PGC1α-UCP1. Both MILK and YOG showed a relative increase in serum PC 15:0_15:0 and LPC 15:0. In contrast, CHE reduced weight gain and increased EE without impacting BAT thermogenesis proteins or serum lipid species. Conclusion: Our study showed that MILK, YOG, and CHE reduced weight gain in mice on a HFD by increasing EE. MILK and YOG also up-regulated BAT thermogenesis, while both additionally altered lipids involved in fat metabolism and inflammation. CHE did not affect BAT thermogenesis and lipid species compared to HFD.

Besides its beneficial effect on weight loss, gastric bypass surgery (GBS) may impact the circulating levels of phospho- and sphingolipids. However, long-term effects have not been explored. To investigate alterations in lipidomic signatures associated with massive weight loss following GBS, we conducted direct infusion tandem mass spectrometry on serum and subcutaneous adipose tissue (SAT) samples collected in a longitudinal cohort of morbid obese patients prior to GBS and 1 year following the surgery. A tissue-specific rearrangement of 13% among over 400 phospholipid and sphingolipid species quantified in serum and SAT was observed 1 year following GBS, with a substantial reduction of ceramide levels and increased amount of hexosylceramides detected in both tissues. The comparison of these new lipidomic profiles with the serum and SAT lipidomes established from an independent cohort of lean and morbid obese subjects revealed that GBS partly restored the lipid alterations associated with morbid obesity.

The study aimed at how dietary milk polar lipids affect gut permeability, systemic inflammation, and lipid metabolism during diet-induced obesity (DIO). C57BL/6J mice (n = 6x3) were fed diets with 34% fat as energy for 15 weeks: (1) modified AIN-93G diet (CO); (2) CO with milk gangliosides (GG); (3) CO with milk phospholipids (MPL). Gut permeability was assessed by FITC-dextran and sugar absorption tests. Intestinal tight junction proteins were evaluated by Western blot. Plasma cytokines were measured by immunoassay. Body composition was assessed by magnetic resonance imaging. Tissue lipid profiles were obtained by thin layer chromatography. Hepatic expression of genes associated with lipid metabolism was assessed by RT-qPCR. MPL increased the efficiency of converting food into body fat and facilitated body fat accumulation compared with CO. MPL and GG did not affect fasting glucose or HOMA-IR during DIO. MPL increased while GG decreased plasma TG compared with CO. MPL decreased phospholipids subclasses in the muscle while increased those in the liver compared with CO. GG and MPL had little effect on hepatic expression of genes associated with lipid metabolism. Compared with CO, MPL decreased polar lipids content in colon mucosa. Small intestinal permeability decreased while colon permeability increased and then recovered during the feeding period. High-fat feeding increased plasma endotoxin after DIO but did not affect plasma cytokines. MPL and GG did not affect plasma endotoxin, adipokines and inflammatory cytokines. After the establishment of obesity, MPL increased gut permeability to large molecules but decreased intestinal absorption of small molecules while GG tended to have the opposite effects. MPL and GG decreased mannitol and sucralose excretions, which peaked at d 45 in the CO group. MPL decreased occludin in jejunum mucosa compared with CO. GG and MPL did not affect zonula occludens-1 in gut mucosa. In conclusion, during DIO, milk GG decreased gut permeability, and had little effect on systemic inflammation and lipid metabolism; MPL facilitated body fat accumulation, decreased gut permeability, did not affect systemic inflammation.

A growing body of research indicates that associations of ceramides and sphingomyelins with mortality depend on the chain length of the fatty acid acylated to the backbone sphingoid base. We examined associations of 8 ceramide and sphingomyelin species with mortality among an American Indian population.

The analysis comprised 2688 participants from the SHFS (Strong Heart Family Study). Plasma ceramide and sphingomyelin species carrying long-chain (ie, 16:0) and very-long-chain (ie, 20:0, 22:0, 24:0) saturated fatty acids were measured by sequential liquid chromatography and mass spectroscopy using samples from 2001 to 2003. Participants were followed for 18.8 years (2001-2020). Associations of ceramides and sphingomyelins with mortality were assessed using Cox models. The mean age of participants was 40.8 years. There were 574 deaths during a median 17.4-year follow-up. Ceramides and sphingomyelins carrying fatty acid 16:0 were positively associated with mortality. Ceramides and sphingomyelins carrying longer fatty acids were inversely associated with mortality. Per SD difference in each ceramide and sphingomyelin species, hazard ratios for death were: 1.68 (95% CI, 1.44-1.96) for ceramide-16 (Cer-16), 0.82 (95% CI, 0.71-0.95) for Cer-20, 0.60 (95% CI, 0.51-0.70) for Cer-22, 0.67 (95% CI, 0.56-0.79) for Cer-24, 1.80 (95% CI-1.57, 2.05) for sphingomyelin-16 (SM-16), 0.54 (95% CI, 0.47-0.62) for SM-20, 0.50 (95% CI, 0.44-0.57) for SM-22, and 0.59 (95% CI, 0.52-0.67) for SM-24.

The direction/magnitude of associations of ceramides and sphingomyelins with mortality differs according to the length of the fatty acid acylated to the backbone sphingoid base.

URL: https://www.clinicatrials.gov; Unique identifier: NCT00005134.

Ceramides are signals of fatty acid excess that accumulate when a cell's energetic needs have been met and its nutrient storage has reached capacity. As these sphingolipids accrue, they alter the metabolism and survival of cells throughout the body including in the heart, liver, blood vessels, skeletal muscle, brain, and kidney. These ceramide actions elicit the tissue dysfunction that underlies cardiometabolic diseases such as diabetes, coronary artery disease, metabolic-associated steatohepatitis, and heart failure. Here, we review the biosynthesis and degradation pathways that maintain ceramide levels in normal physiology and discuss how the loss of ceramide homeostasis drives cardiometabolic pathologies. We highlight signaling nodes that sense small changes in ceramides and in turn reprogram cellular metabolism and stimulate apoptosis. Finally, we evaluate the emerging therapeutic utility of these unique lipids as biomarkers that forecast disease risk and as targets of ceramide-lowering interventions that ameliorate disease.

Elevated concentrations of palmitate in serum of obese individuals can impair endothelial function, contributing to development of cardiovascular disease. Although several molecular mechanisms of palmitate-induced endothelial dysfunction have been proposed, there is no consensus on what signaling event is the initial trigger of detrimental palmitate effects. Here we report that inhibitors of ER stress or ceramid synthesis can rescue palmitate-induced autophagy impairment in macro- and microvascular endothelial cells. Furthermore, palmitate-induced cholesterol synthesis was reverted using these inhibitors. Similar to cell culture data, autophagy markers were increased in serum of obese individuals. Subsequent lipidomic analysis revealed that palmitate changed the composition of membrane phospholipids in endothelial cells and that these effects were not reverted upon application of above-mentioned inhibitors. However, ER stress inhibition in palmitate-treated cells enhanced the synthesis of trilglycerides and restored ceramide levels to control condition. Our results suggest that palmitate induces ER-stress presumably by shift in membrane architecture, leading to impaired synthesis of triglycerides and enhanced production of ceramides and cholesterol, which altogether enhances lipotoxicity of palmitate in endothelial cells.

A randomized clinical trial to evaluate the effect of a Mediterranean-style diet on vascular health indices such as endothelial function indices, serum lipid and ceramide plasma and some adipokine serum levels. We recruited all consecutive patients at high risk of cardiovascular diseases admitted to the Internal Medicine and Stroke Care ward at the University Hospital of Palermo between September 2017 and December 2020.

The enrolled subjects, after the evaluation of the degree of adherence to a dietary regimen of the Mediterranean-style diet, were randomised to a Mediterranean Diet (group A) assessing the adherence to a Mediterranean-style diet at each follow up visit (every three months) for the entire duration of the study (twelve months) and to a Low-fat diet (group B) with a dietary "counselling" starting every three months for the entire duration of the study (twelve months).The aims of the study were to evaluate: the effects of adherence to Mediterranean Diet on some surrogate markers of vascular damage, such as endothelial function measured by means of the reactive hyperaemia index (RHI) and augmentation index (AIX), at the 6-(T1) and 12-month (T2) follow-ups; the effects of adherence to Mediterranean Diet on the lipidaemic profile and on serum levels of ceramides at T1 and T2 follow-ups; the effects of adherence to Mediterranean Diet on serum levels of visfatin, adiponectin and resistin at the 6- and 12-month follow-ups.

A total of 101 patients were randomised to a Mediterranean Diet style and 52 control subjects were randomised to a low-fat diet with a dietary "counselling". At the six-month follow-up (T1), subjects in the Mediterranean Diet group showed significantly lower mean serum total cholesterol levels, and significantly higher increase in reactive hyperaemia index (RHI) values compared to the low-fat diet group. Patients in the Mediterranean Diet group also showed lower serum levels of resistin and visfatin at the six-month follow-up compared to the control group, as well as higher values ​​of adiponectin, lower values of C24:0, higher values of C22:0 and higher values of the C24:0/C16:0 ratio. At the twelve-month follow-up (T2), subjects in the Mediterranean Diet group showed lower serum total cholesterol levels and lower serum LDL cholesterol levels than those in the control group. At the twelve-month follow-up, we also observed a further significant increase in the mean RHI in the Mediterranean Diet group, lower serum levels of resistin and visfatin, lower values of C24:0 and of C:18:0,and higher values of the C24:0/C16:0 ratio.

The findings of our current study offer a further possible explanation with regard to the beneficial effects of a higher degree of adherence to a Mediterranean-style diet on multiple cardiovascular risk factors and the underlying mechanisms of atherosclerosis. Moreover, these findings provide an additional plausible interpretation of the results from observational and cohort studies linking high adherence to a Mediterranean-style diet with lower total mortality and a decrease in cardiovascular events and cardiovascular mortality.

ClinicalTrials.gov Identifier: NCT04873167. https://classic.clinicaltrials.gov/ct2/show/NCT04873167.

Insulin resistance (IR), linked to air pollution, is an initial stage of early-onset Type 2 diabetes mellitus (T2DM). While ceramide metabolism plays an important role in IR pathogenesis, the effects of air pollution on this process and its mechanisms remain unclear. We recruited young adults aged 18-30 years to a panel study in Wuhan, China. Using personal portable devices and stationary monitoring stations, we tracked particulate matter with aerodynamic diameters≤ 2.5 µm (PM2.5) and Ozone (O3) levels. Liquid chromatography/mass spectrometry (LC-MS) based metabolomics quantified ceramide metabolism, and Illumina Infinium Human Methylation 850 kBeadChip assay measured deoxyribonucleic acid (DNA) methylation. Linear mixed-effects models assessed relationships of air pollution with i) IR indexes, ii) ceramide metabolism, and iii) DNA methylation. Mediation analysis was subsequently performed to evaluate the potential mediating effect of DNA methylation in the association between air pollution and ceramide metabolism. PM2.5 and O3 were associated with elevated IR. Specifically, each 10 μg/m3 increase in PM2.5 and O3 at lag0-12 h significantly increased triglyceride‑glucose index (TyG index) and TyG-BMI (TyG - Body mass index) by 0.88%, 0.89% and 0.26%, 0.26%, respectively. Furthermore, levels of eight ceramides were altered by air pollution exposure, and nine methylated CpG sites in inflammation genes mediated the effects of air pollution on ceramide metabolism. Our findings imply the existence of a novel mechanism connecting air pollution to IR.

Sphingolipids are implicated in neurodegeneration and neuroinflammation. We assessed the potential role of circulating ceramides and sphingomyelins in subclinical brain pathology by investigating their association with brain magnetic resonance imaging (MRI) measures and circulating biomarkers of brain injury, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in the Cardiovascular Health Study (CHS), a large and intensively phenotyped cohort of older adults.

Brain MRI was offered twice to CHS participants with a mean of 5 years between scans, and results were available from both time points in 2,116 participants (mean age 76 years; 40% male; and 25% APOE ε4 allele carriers). We measured 8 ceramide and sphingomyelin species in plasma samples and examined the associations with several MRI, including worsening grades of white matter hyperintensities and ventricular size, number of brain infarcts, and measures of brain atrophy in a subset with quantitative measures. We also investigated the sphingolipid associations with serum NfL and GFAP.

In the fully adjusted model, higher plasma levels of ceramides and sphingomyelins with a long (16-carbon) saturated fatty acid were associated with higher blood levels of NfL [β = 0.05, false-discovery rate corrected P (PFDR) = 0.004 and β = 0.06, PFDR = < 0.001, respectively]. In contrast, sphingomyelins with very long (20- and 22-carbon) saturated fatty acids tended to have an inverse association with levels of circulating NfL. In secondary analyses, we found an interaction between ceramide d18:1/20:0 and sex (P for interaction = <0.001), such that ceramide d18:1/20:0 associated with higher odds for infarcts in women [OR = 1.26 (95%CI: 1.07, 1.49), PFDR = 0.03]. We did not observe any associations with GFAP blood levels, white matter grade, ventricular grade, mean bilateral hippocampal volume, or total brain volume.

Overall, our comprehensive investigation supports the evidence that ceramides and sphingomyelins are associated with increased aging brain pathology and that the direction of association depends on the fatty acid attached to the sphingosine backbone.

Although sickle cell disease (SCD) and its manifestations have been associated with various lipid alterations, there are a few studies exploring the impact of sphingolipids in SCD. In this study, we determined plasma ceramide (Cer) and sphingomyelin (CerPCho) species and investigated their association with the crisis in SCD. SCD patients (N = 27) suffering from vaso-occlusive crisis (VOC) or acute chest syndrome (ACS) were involved in this study. Blood samples were drawn at crisis and later at steady state periods. Clinical history, white blood cell count (WBC), C-reactive protein and lactate dehydrogenase (LDH) levels were recorded. 16:0, 18:0, 20:0, 22:0 Cer and 16:0, 18:0, 24:0 CerPCho were measured via LC-MS/MS. All measured Cer and CerPCho levels of SCD patients at crisis and steady-state were found to be similar. Inflammation-related parameters were significantly higher in patients with ACS compared to single-site VOC. Patients with multiple-site VOC were found to have significantly lower sphingolipid levels compared with those with single-site VOC, at crisis (16, 18, 24 CerPCho and 18, 22 Cer) and at steady-state (24:0 CerPCho and 18 Cer). Our results show that sphingolipid levels in SCD patients are similar during crisis and at steady state. However, lower sphingolipid levels appear to be associated with the development of multiple-site VOC. Since the differences were observed at both crisis and steady-state, sphingolipid level could be an underlying factor associated with crisis characteristics in patients with SCD.

To prospectively investigate associations of plasma sphingolipids with insulin sensitivity, β-cell function, and incident diabetes in the Japanese American Community Diabetes Study.

Baseline plasma samples from adults without diabetes (n = 349; mean age 56.7 years, 51 % men) were assayed for circulating ceramide and sphingomyelin species. Adjusted regression models examined cross-sectional and longitudinal associations with insulin sensitivity (HOMA2-%S), β-cell function (oral disposition index: DIo) and with incident diabetes over 5 years follow-up. Concentrations of four species (Ceramide C16:0, C18:0, C20:0, and C22:0) were inversely associated with HOMA2-%S at baseline (all P values < 0.05, Q values < 0.05) and change in HOMA2-%S over 5 years (all P values < 0.05, Q values < 0.05). No sphingolipids were associated with baseline or change in DIo. Of the four species associated with HOMA2-%S, only Ceramide C18:0 was significantly and positively associated with incident diabetes (RR/1SD 1.44, 95 % CI 1.10-1.80, P = 0.006, Q = 0.024). The association of plasma Ceramide C18:0 with the risk of diabetes was partially mediated by change in HOMA2-%S between baseline and 5 years (mediation proportion: 61.5 %, 95 % CI 21.1%-212.5 %).

Plasma Ceramide C18:0 was associated with higher risk of incident diabetes which was partially mediated through a decrease in insulin sensitivity between baseline and five years. Circulating Ceramide C18:0 could be a potential biomarker for identifying those at risk of developing diabetes.

Gouty arthritis (GA) is a common inflammatory disease caused by deposition of monosodium urate (MSU) crystals in diarthrodial joints. GA attacks commonly involved in joint with red, swollen, heat and pain, and often happened in unilateral foot-first metatarsophalangeal. Accumulated studies have proved that lipids play critical roles in biological processes and lipids biomarkers can substitute for the diagnosis of various diseases.

Herein, shotgun lipidomics was used to quantitatively analyze serum lipidomes of a gouty model which was induced by injecting MSU crystals and feeding high-fat diet with/without treatment with allopurinol. Meanwhile, ELISA kit was used to detect mouse serum levels of inflammatory cytokines (eg, tumor necrosis factor-α, interleukin 1 beta) and HE staining was used to observe the infiltration of inflammatory cells in the foot pad.

A total of 9 types of serum lipids were detected in lipidomics by shotguns, and the result of NMDS' analysis demonstrated significant differences in lipids profiles between the control and model group. It is worth noting that lipid abnormality in GA (such as Ceramide (Cer), sphingomyelin (SM), 4-hydroxyalkenals (HNE), phosphatidylinositol (PI), ethanolamine glycerophospholipid (PE), etc.) is related with phospholipid and energy metabolism, and allopurinol treatment could correct the aberrant metabolism of lipid to some extent.

Our results indicated that various aberrant lipid metabolisms were present in the established gouty model, and allopurinol treatment could relief this aberrant metabolism of lipids to some degree.

Hyperglycemia 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.

Liquid 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.

Increased 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.

These 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.

Higher levels of palmitoyl sphingomyelin (PSM, synonymous with sphingomyelin 16:0) are associated with an increased risk of cardiovascular disease (CVD) in people with diabetes. Whether circulating PSM levels can practically predict the long-term risk of CVD and all-cause death remains unclear. This study aimed to investigate whether circulating PSM is a real predictor of CVD death in Chinese adults with or without diabetes.

A total of 286 and 219 individuals with and without diabetes, respectively, from the original Da Qing Diabetes Study were enrolled. Blood samples collected in 2009 were used as a baseline to assess circulating PSM levels. The outcomes of CVD and all-cause death were followed up from 2009 to 2020, and 178 participants died, including 87 deaths due to CVD. Cox proportional hazards regression was used to estimate HRs and their 95% CIs for the outcomes.

Fractional polynomial regression analysis showed a linear association between baseline circulating PSM concentration (log-2 transformed) and the risk of all-cause and CVD death (p < 0.001), but not non-CVD death (p > 0.05), in all participants after adjustment for confounders. When the participants were stratified by PSM-tertile, the highest tertile, regardless of diabetes, had a higher incidence of CVD death (41.5 vs. 14.7 and 22.2 vs. 2.9 per 1000 person-years in patients with and without diabetes, respectively, all log-rank p < 0.01). Individuals with diabetes in the highest tertile group had a higher risk of CVD death than those in the lowest tertile (HR = 2.73; 95%CI, 1.20-6.22).

Elevated PSM levels are significantly associated with a higher 10-year risk of CVD death, but not non-CVD death, in Chinese adults with diabetes. These findings suggest that PSM is a potentially useful long-term predictor of CVD death in individuals with diabetes.

Background: Elevated Phospholipids (PLs) and sphingolipid (SM) metabolism relates to with poor clinical status and adverse outcome of end-stage kidney disease patients undergoing peritoneal dialysis (PD). Studies have suggested that the use of hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) (Roxadustat) is associated with altered lipid metabolism. Observing on how PLs and SMs changes after the HIF-PHI treatment in PD patients may help understand the possible effect of HIF-PHI on PD patients besides correcting of anemia. Materials and methods: Stable peritoneal dialysis (PD) patients treated with Roxadustat for over 3 months were included. Phospholipid and sphingolipid metabolism were measured before and after treatment. Results: 25 PD patients were included. Overall, phospholipid and sphingolipid metabolism showed a decreasing trend after HIF-PHI treatment. Levels of LysoPC (20:0), 1,2-dilinoleoyl-sn-glycero-3-phosphocholine [CisPC (DLPC) (18:2)], lysophosphatidylethanolamine (LysoPE) (14:0), and sphingomyelin (d18:1/17:0) (17:0) were significantly decreased (all p < 0.05). Further regression analyses confirmed the significant relationship between the increased of hemoglobin levels and the decrease in egg lyso PC: phosphatidylethanolamines (PE) (16:0-18:1), PE (16:0-18:2), PE (16:0-22:6), PE (18:0-20:4), PE (18:0-18:2), LysoPE (18:0), LysoPE (18:1), and phosphatidylcholine (PC) (18:1-18:0). Conclusion: This study demonstrated that phospholipid and sphingolipid metabolism decreased after administration of HIF-PHI and was associated with improvement of anemia.

Ceramide synthases (CerS) catalyze ceramide formation via N-acylation of a sphingoid base with a fatty acyl-CoA and are attractive drug targets for treating numerous metabolic diseases and cancers. Here, we present the cryo-EM structure of a yeast CerS complex, consisting of a catalytic Lac1 subunit and a regulatory Lip1 subunit, in complex with C26-CoA substrate. The CerS holoenzyme exists as a dimer of Lac1-Lip1 heterodimers. Lac1 contains a hydrophilic reaction chamber and a hydrophobic tunnel for binding the CoA moiety and C26-acyl chain of C26-CoA, respectively. Lip1 interacts with both the transmembrane region and the last luminal loop of Lac1 to maintain the proper acyl chain binding tunnel. A lateral opening on Lac1 serves as a potential entrance for the sphingoid base substrate. Our findings provide a template for understanding the working mechanism of eukaryotic ceramide synthases and may facilitate the development of therapeutic CerS modulators.

Sphingolipids, including ceramides and sphingomyelins, may influence the pathophysiology and risk of sudden cardiac death (SCD) through multiple biological activities. Whether the length of the fatty acid acylated to plasma sphingolipid species is associated with SCD risk is not known.

To determine whether the saturated fatty acid length of plasma ceramides and sphingomyelins influences the association with SCD risk.

In this cohort study, multivariable Cox proportional hazards regression models were used to examine the association of sphingolipid species with SCD risk. The study population included 4612 participants in the Cardiovascular Health Study followed up prospectively for a median of 10.2 (IQR, 5.5-11.6) years. Baseline data were collected from January 1992 to December 1995 during annual examinations. Data were analyzed from February 11, 2020, to September 9, 2023.

Eight plasma sphingolipid species (4 ceramides and 4 sphingomyelins) with saturated fatty acids of 16, 20, 22, and 24 carbons.

Association of plasma ceramides and sphingomyelins with saturated fatty acids of different lengths with SCD risk.

Among the 4612 CHS participants included in the analysis (mean [SD] age, 77 [5] years; 2724 [59.1%] women; 6 [0.1%] American Indian; 4 [0.1%] Asian; 718 [15.6%] Black; 3869 [83.9%] White, and 15 [0.3%] Other), 215 SCD cases were identified. In adjusted Cox proportional hazards regression analyses, plasma ceramides and sphingomyelins with palmitic acid (Cer-16 and SM-16) were associated with higher SCD risk per higher SD of log sphingolipid levels (hazard ratio [HR] for Cer-16, 1.34 [95% CI, 1.12-1.59]; HR for SM-16, 1.37 [95% CI, 1.12-1.67]). Associations did not differ by baseline age, sex, race, or body mass index. No significant association of SCD with sphingolipids with very-long-chain saturated fatty acids was observed after correction for multiple testing (HR for ceramide with arachidic acid, 1.06 [95% CI, 0.90-1.24]; HR for ceramide with behenic acid, 0.92 [95% CI, 0.77-1.10]; HR for ceramide with lignoceric acid, 0.92 [95% CI, 0.77-1.09]; HR for sphingomyelin with arachidic acid, 0.83 [95% CI, 0.71-0.98]; HR for sphingomyelin with behenic acid, 0.84 [95% CI, 0.70-1.00]; HR for sphingomyelin with lignoceric acid, 0.86 [95% CI, 0.72-1.03]).

The findings of this large, population-based cohort study of SCD identified that higher plasma levels of Cer-16 and SM-16 were associated with higher risk of SCD. Future studies are needed to examine the underlying mechanism of these associations.

Type 2 diabetes mellitus (T2DM) has become a major health problem, threatening the quality of life of nearly 500 million patients worldwide. As a typical multifactorial metabolic disease, T2DM involves the changes and interactions of various metabolic pathways such as carbohydrates, amino acid, and lipids. It has been suggested that metabolites are not only the endpoints of upstream biochemical processes, but also play a critical role as regulators of disease progression. For example, excess free fatty acids can lead to reduced glucose utilization in skeletal muscle and induce insulin resistance; metabolism disorder of branched-chain amino acids contributes to the accumulation of toxic metabolic intermediates, and promotes the dysfunction of β-cell mitochondria, stress signal transduction, and apoptosis. In this paper, we discuss the role of metabolites in the pathogenesis of T2DM and their potential as biomarkers. Finally, we list the effects of anti-hyperglycemic drugs on serum/plasma metabolic profiles.

Ceramides are lipid molecules involved in inflammation-related signaling. Recent studies have shown that higher amounts of specific circulating ceramides and their ratios are associated with future development of cardiovascular (CV) disease (CVD). We examined the associations between serum ceramide levels with CVD, kidney failure, and all-cause mortality in individuals with long-standing type 1 diabetes (T1D). We included 662 participants with T1D and 6-year follow-up, with a mean age of 55 years and mean diabetes duration of 33 years. Baseline serum samples were analyzed using liquid chromatography-mass spectrometry. Six predefined ceramide levels were measured, and predefined ratios were calculated. Adjusted Cox regression analyses on ceramide levels in relation to future CV events (CVE), kidney failure, and all-cause mortality were performed, with and without adjustment for age, sex, BMI, LDL, triglycerides, systolic blood pressure, HbA1c, history of CVD, smoking status, statin use, estimated glomerular filtration rate (eGFR), and urinary albumin excretion rate (UAER). The ceramide ratio cer(d18:1/18:0)/cer(d18:1/24:0) was significantly associated with risk of CVE (hazard ratio [HR] = 1.33, P = 0.01) and all-cause mortality (HR = 1.48, P = 0.01) before and after adjustments. All five investigated ceramide ratios were associated with kidney failure, before adjusting for the kidney markers eGFR and UAER. In this study, we demonstrate specific ceramides and ratios associated with 6-year cardiovascular risk and all-cause mortality in a T1D cohort. This highlights the strength of ceramide association with vascular complications and presents a new potential tool for early risk assessment if validated in other cohorts.

Improved tools for assessing risk for diabetes complication before onset will help in complication prevention. We investigated a set of six predefined ceramides and their ratios versus 6-year outcomes of cardiovascular events, kidney failure, and all-cause mortality in people with long-standing type 1 diabetes, using Cox regression with and without adjustment for potential confounders. We found that several ceramides and ceramide ratios associated with cardiovascular events and all-cause mortality. The ratio of cer(d18:1/18:0)/cer(d18:1/24:0) was an especially robust marker. These finding show that ceramides can be biomarkers of cardiovascular disease and all-cause mortality in individuals with long-standing type 1 diabetes.

Evidence of impact of ambient oxidant pollution on cardiometabolic responses remains limited. We aimed to examine associations of oxidant pollutants with cardiometabolic responses, and effect modification by ceramides. During 2019-2020, 152 healthy adults were visited 4 times in Beijing, China, and indicators of ceramides, glucose homeostasis, and vascular function were measured. We found significant increases in ceramides of 13.9% (p = 0.020) to 110.1% (p = 0.005) associated with an interquartile increase in oxidant pollutants at prior 1-7 days. Exposure to oxidant pollutants was also related to elevations in insulin and reductions in adiponectin, and elevations in systolic and diastolic blood pressure. Further, stratified analyses revealed larger changes in oxidant pollutant related cardiometabolic responses among participants with higher ceramide levels compared to those with lower levels. Our findings suggested cardiometabolic effects associated with exposure to oxidant pollutants, which may be modified by ceramide levels.

Specific ceramides have been identified as risk markers for cardiovascular disease (CVD) years before onset of disease. Treatment with the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide has been shown to induce beneficial changes in the lipid profile and reduce the risk of CVD. Reducing lipotoxic lipids with an antidiabetic drug therapy could be a path towards precision medicine approaches for the treatment of complications to diabetes. In this post-hoc study, an investigation was carried out on the effect of liraglutide on CVD-risk associated ceramides in two randomized clinical trials including participants with type 2 diabetes (T2D).

This study analyzed plasma samples from two independent randomized placebo-controlled clinical trials. The first trial, Antiproteinuric Effects of Liraglutide Treatment (LirAlbu12) followed a crossover design where 27 participants were treated for 12 weeks with either liraglutide (1.8 mg/d) or placebo, followed by a four-week washout period, and then another 12 weeks of the other treatment. The second clinical trial, Effect of Liraglutide on Vascular Inflammation in Type-2 Diabetes (LiraFlame26), lasted for 26 weeks and followed a parallel design, where 102 participants were randomized 1:1 to either liraglutide or placebo. Heresix prespecified plasma ceramides were measured using liquid chromatography mass spectrometry and assessed their changes using linear mixed models. Possible confounders were assessed with mediation analyses.

In the LiraFlame26 trial, 26-week treatment with liraglutide resulted in a significant reduction of two ceramides associated with CVD risk, C16 Cer and C24:1 Cer (p < 0.05) compared to placebo. None of the remaining ceramides showed statistically significant changes in response to liraglutide treatment compared to placebo. Significant changes in ceramides were not found after 12-weeks of liraglutide treatment in the LirAlbu12 trial. Mediation analyses showed that weight loss did not affect ceramide reduction.

It was demonstrated that treatment with liraglutide resulted in a reduction in C16 Cer and C24:1 Cer after 26 weeks of treatment. These findings suggest the GLP-1RA can be used to modulate ceramides in addition to its other properties.

Clinicaltrial.gov identifier: NCT02545738 and NCT03449654.

Changes in the maternal metabolome, and specifically the maternal lipidome, that occur during pregnancy are relatively unknown. The objective of this investigation was to evaluate the effects of pregnancy on sphingolipid levels using metabolomics analysis followed by confirmational, targeted quantitative analysis. We focused on three subclasses of sphingolipids: ceramides, sphingomyelins, and sphingosines. Forty-seven pregnant women aged 18 to 50 years old participated in this study. Blood samples were collected on two study days for metabolomics analysis. The pregnancy samples were collected between 25 and 28 weeks of gestation and the postpartum study day samples were collected ≥3 months postpartum. Each participant served as their own control. These samples were analyzed using a Ultra-performance liquid chromatography/mass spectroscopy/mass spectroscopy (UPLC/MS/MS) assay that yielded semi-quantitative peak area values that were used to compare sphingolipid levels between pregnancy and postpartum. Following this lipidomic analysis, quantitative LC/MS/MS targeted/confirmatory analysis was performed on the same study samples. In the metabolomic analysis, 43 sphingolipid metabolites were identified and their levels were assessed using relative peak area values. These profiled sphingolipids fell into three categories: ceramides, sphingomyelins, and sphingosines. Of the 43 analytes measured, 35 were significantly different during pregnancy (p < 0.05) (including seven ceramides, 26 sphingomyelins, and two sphingosines) and 32 were significantly higher during pregnancy compared to postpartum. Following metabolomics, a separate quantitative analysis was performed and yielded quantified concentration values for 23 different sphingolipids, four of which were also detected in the metabolomics study. Quantitative analysis supported the metabolomics results with 17 of the 23 analytes measured found to be significantly different during pregnancy including 11 ceramides, four sphingomyelins, and two sphingosines. Fourteen of these were significantly higher during pregnancy. Our data suggest an overall increase in plasma sphingolipid concentrations with possible implications in endothelial function, gestational diabetes mellitus (GDM), intrahepatic cholestasis of pregnancy, and fetal development. This study provides evidence for alterations in maternal sphingolipid metabolism during pregnancy.

Sphingolipids are a family of circulating lipids with regulatory and signaling roles that are strongly associated with both eGFR and cardiovascular disease. Patients with chronic kidney disease (CKD) are at high risk for cardiovascular events, and have different plasma concentrations of certain plasma sphingolipids compared to patients with normal kidney function. We hypothesize that circulating sphingolipids partially mediate the associations between eGFR and cardiovascular events.

We measured the circulating concentrations of 8 sphingolipids, including 4 ceramides and 4 sphingomyelins with the fatty acids 16:0, 20:0, 22:0, and 24:0, in plasma from 3,463 participants in a population-based cohort (Cardiovascular Health Study) without prevalent cardiovascular disease. We tested the adjusted mediation effects by these sphingolipids of the associations between eGFR and incident cardiovascular disease via quasi-Bayesian Monte Carlo method with 2,000 simulations, using a Bonferroni correction for significance.

The mean (±SD) eGFR was 70 (±16) mL/min/1.73 m2; 62% of participants were women. Lower eGFR was associated with higher plasma ceramide-16:0 and sphingomyelin-16:0, and lower ceramides and sphingomyelins-20:0 and -22:0. Lower eGFR was associated with risk of incident heart failure and ischemic stroke, but not myocardial infarction. Five of eight sphingolipids partially mediated the association between eGFR and heart failure. The sphingolipids associated with the greatest proportion mediated were ceramide-16:0 (proportion mediated 13%, 95% CI 8-22%) and sphingomyelin-16:0 (proportion mediated 10%, 95% CI 5-17%). No sphingolipids mediated the association between eGFR and ischemic stroke.

Plasma sphingolipids partially mediated the association between lower eGFR and incident heart failure. Altered sphingolipids metabolism may be a novel mechanism for heart failure in patients with CKD.

This study was supported by T32 DK007467 and a KidneyCure Ben J. Lipps Research Fellowship (Dr. Lidgard). Sphingolipid measurements were supported by R01 HL128575 (Dr. Lemaitre) and R01 HL111375 (Dr. Hoofnagle) from the National Heart, Lung, and Blood Institute (NHLBI).

Non-alcoholic fatty liver disease (NAFLD), is the most common cause of chronic liver disease, affecting 24% of the global population. Accumulating evidence demonstrates that copper deficiency (CuD) is implicated in the development of NAFLD, besides, high fructose consumption by promoting inflammation contributes to NAFLD. However, how CuD and/or fructose (Fru) causes NAFLD is not clearly delineated. The present study aims to investigate the role of CuD and/or fructose supplement on hepatic steatosis and hepatic injury. We established a CuD rat model by feeding weaning male Sprague-Dawley rats for 4 weeks with CuD diet. Fructose was supplemented in drinking water. We found the promoting role of CuD or Fructose (Fru) in the progress of NAFLD, which was aggravated by combination of the two. Furthermore, we presented the alteration of hepatic lipid profiles (including content, composition, and saturation), especially ceramide (Cer), cardiolipin (CL), phosphatidylcholine (PC) and phosphatidylethanolamine (PE) was closely associated with CuD and/or Fru fed induced-NAFLD in rat models. In conclusion, insufficient copper intake or excessive fructose supplement resulted in adverse effects on the hepatic lipid profile, and fructose supplement causes a further hepatic injury in CuD-induced NAFLD, which illuminated a better understanding of NAFLD.

Disruption of mitochondrial function and protein homeostasis plays a central role in aging. However, how these processes interact and what governs their failure in aging remain poorly understood. Here, we showed that ceramide biosynthesis controls the decline in mitochondrial and protein homeostasis during muscle aging. Analysis of transcriptome datasets derived from muscle biopsies obtained from both aged individuals and patients with a diverse range of muscle disorders revealed that changes in ceramide biosynthesis, as well as disturbances in mitochondrial and protein homeostasis pathways, are prevalent features in these conditions. By performing targeted lipidomics analyses, we found that ceramides accumulated in skeletal muscle with increasing age across Caenorhabditis elegans, mice, and humans. Inhibition of serine palmitoyltransferase (SPT), the rate-limiting enzyme of the ceramide de novo synthesis, by gene silencing or by treatment with myriocin restored proteostasis and mitochondrial function in human myoblasts, in C. elegans, and in the skeletal muscles of mice during aging. Restoration of these age-related processes improved health and life span in the nematode and muscle health and fitness in mice. Collectively, our data implicate pharmacological and genetic suppression of ceramide biosynthesis as potential therapeutic approaches to delay muscle aging and to manage related proteinopathies via mitochondrial and proteostasis remodeling.

Resveratrol (RSV) is a phenolic compound with strong antioxidant activity, which is generally associated with the beneficial effects of wine on human health. All resveratrol-mediated benefits exerted on different systems and pathophysiological conditions are possible through resveratrol's interactions with different biological targets, along with its involvement in several key cellular pathways affecting cardiometabolic (CM) health. With regard to its role in oxidative stress, RSV exerts its antioxidant activity not only as a free radical scavenger but also by increasing the activity of antioxidant enzymes and regulating redox genes, nitric oxide bioavailability and mitochondrial function. Moreover, several studies have demonstrated that some RSV effects are mediated by changes in sphingolipids, a class of biolipids involved in a number of cellular functions (e.g., apoptosis, cell proliferation, oxidative stress and inflammation) that have attracted interest as emerging critical determinants of CM risk and disease. Accordingly, this review aimed to discuss the available data regarding the effects of RSV on sphingolipid metabolism and signaling in CM risk and disease, focusing on oxidative stress/inflammatory-related aspects, and the clinical implications of this relationship.

Ceramides (CERs) are key intermediate sphingolipids implicated in contributing to mitochondrial dysfunction and the development of multiple metabolic conditions. Despite the growing evidence of CER role in disease risk, kinetic methods to measure CER turnover are lacking, particularly using in vivo models. The utility of orally administered 13C3, 15N l-serine, dissolved in drinking water, was tested to quantify CER 18:1/16:0 synthesis in 10-week-old male and female C57Bl/6 mice. To generate isotopic labeling curves, animals consumed either a control diet or high-fat diet (HFD; n = 24/diet) for 2 weeks and varied in the duration of the consumption of serine-labeled water (0, 1, 2, 4, 7, or 12 days; n = 4 animals/day/diet). Unlabeled and labeled hepatic and mitochondrial CERs were quantified using liquid chromatography tandem MS. Total hepatic CER content did not differ between the two diet groups, whereas total mitochondrial CERs increased with HFD feeding (60%, P < 0.001). Within hepatic and mitochondrial pools, HFD induced greater saturated CER concentrations (P < 0.05) and significantly elevated absolute turnover of 16:0 mitochondrial CER (mitochondria: 59%, P < 0.001 vs. liver: 15%, P = 0.256). The data suggest cellular redistribution of CERs because of the HFD. These data demonstrate that a 2-week HFD alters the turnover and content of mitochondrial CERs. Given the growing data on CERs contributing to hepatic mitochondrial dysfunction and the progression of multiple metabolic diseases, this method may now be used to investigate how CER turnover is altered in these conditions.