Blood sphingolipidomics in healthy humans: impact of sample collection methodology

Hammad, Samar M.; Pierce, Jason S.; Soodavar, Farzan; Smith, Kent J.; Gadban, Mohammed M. Al; Rembiesa, Barbara; Klein, Richard L.; Hannun, Yusuf A.; Bielawski, Jacek; Bielawska, Alicja

doi:10.1194/jlr.d008532

Cited by 279 publications

(352 citation statements)

References 56 publications

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“…A number of cross‐sectional studies have reported sex differences in circulating ceramides (Hammad et al ., 2010; Bui et al ., 2012; Ishikawa et al ., 2013; Weir et al ., 2013). Typically, women have higher blood levels of most ceramides compared with men.…”

Section: Discussionmentioning

confidence: 99%

“…Because the collection of blood is noninvasive and more acceptable and feasible for serial measures, we initially focused on the characterization of ceramides and metabolites in this medium. Lastly, ceramides are hydrophobic, so they are carried on lipoproteins in the blood, with the greatest concentrations in VLDL and LDL (Hammad et al ., 2010) and the ceramide transporter (CERT) (Mencarelli et al ., 2010). The composition and quantification of the specific acyl chain lengths of ceramides and DHCer on lipoproteins or CERT may differ by age and with disease onset.…”

Section: Discussionmentioning

confidence: 99%

“…Yet, compared to other lipids (e.g., cholesterol, triglycerides), there are little data on ceramides at the population level and the intra‐ and interindividual changes in levels of specific carbon chain lengths by age, sex, race, and disease status. Previous, carefully validated, studies have utilized small sample sizes of 10–15 individuals aged 20–40 years (Hammad et al ., 2010; Bui et al ., 2012) or have used pooled samples (Quehenberger et al ., 2010). A recent population‐based study performed plasma lipid profiling in over 1000 individuals, median age of 36, enrolled in the San Antonio Family Heart Study (Weir et al ., 2013).…”

Section: Introductionmentioning

confidence: 99%

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Demographic and clinical variables affecting mid‐ to late‐life trajectories of plasma ceramide and dihydroceramide species

et al. 2015

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SummaryIt has been increasingly recognized at the basic science level that perturbations in ceramide metabolism are associated with the development and progression of many age‐related diseases. However, the translation of this work to the clinic has lagged behind. Understanding the factors longitudinally associated with plasma ceramides and dihydroceramides (DHCer) at the population level and how these lipid levels change with age, and by sex, is important for the clinical development of future therapeutics and biomarkers focused on ceramide metabolism. We, therefore, examined factors cross‐sectionally and longitudinally associated with plasma concentrations of ceramides and DHCer among Baltimore Longitudinal Study of Aging participants (n = 992; 3960 total samples), aged 55 years and older, with plasma at a mean of 4.1 visits (range 2–6). Quantitative analyses were performed on a high‐performance liquid chromatography‐coupled electrospray ionization tandem mass spectrometer. Linear mixed models were used to assess the relationships between plasma ceramide and DHCer species and demographics, diseases, medications, and lifestyle factors. Women had higher plasma concentrations of most ceramide and DHCer species and showed steeper trajectories of age‐related increases compared to men. Ceramides and DHCer were more associated with waist–hip ratio than body mass index. Plasma cholesterol and triglycerides, prediabetes, and diabetes were associated with ceramides and DHCer, but the relationship showed specificity to the acyl chain length and saturation. These results demonstrate the importance of examining the individual species of ceramides and DHCer, and of establishing whether intra‐individual age‐ and sex‐specific changes occur in synchrony to disease onset and progression.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Demographic and clinical variables affecting mid‐ to late‐life trajectories of plasma ceramide and dihydroceramide species

et al. 2015

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“…Independent of potential confounders, sex differences were confirmed for C16:0, C18:0, C20:0, C24:1 ceramides and C20:0 dihydroceramide, with men showing a significantly stronger association between higher levels of ceramides and poor aerobic capacity as compared to women. This interesting finding is in keeping with previous cross‐sectional studies that reported gender differences in plasma levels of ceramides, with women generally showing higher concentrations of ceramides then men (Hammad et al ., 2010; Bui et al ., 2012; Ishikawa et al ., 2013; Weir et al ., 2013). Longitudinal sex differences in the levels of ceramides with aging were also previously described in BLSA population, with women showing a steeper trajectory of increase than men (Mielke et al ., 2015).…”

Section: Discussionmentioning

confidence: 99%

Circulating ceramides are inversely associated with cardiorespiratory fitness in participants aged 54–96 years from the Baltimore Longitudinal Study of Aging

Fabbri

Simonsick

et al. 2016

Aging Cell

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SummaryCardiorespiratory fitness (VO 2 peak) declines with age and is an independent risk factor for morbidity and mortality in older adults. Identifying biomarkers of low fitness may provide insight for why some individuals experience an accelerated decline of aerobic capacity and may serve as clinically valuable prognostic indicators of cardiovascular health. We investigated the relationship between circulating ceramides and VO 2 peak in 443 men and women (mean age of 69) enrolled in the Baltimore Longitudinal Study of Aging (BLSA). Individual species of ceramide were quantified by HPLC–tandem mass spectrometry. VO 2 peak was measured by a graded treadmill test. We applied multiple regression models to test the associations between ceramide species and VO 2 peak, while adjusting for age, sex, blood pressure, serum LDL, HDL, triglycerides, and other covariates. We found that higher levels of circulating C18:0, C20:0, C24:1 ceramides and C20:0 dihydroceramides were strongly associated with lower aerobic capacity (P < 0.001, P < 0.001, P = 0.018, and P < 0.001, respectively). The associations held true for both sexes (with men having a stronger association than women, P value for sex interaction <0.05) and were unchanged after adjusting for confounders and multiple comparison correction. Interestingly, no significant association was found for C16:0, C22:0, C24:0, C26:0, and C22:1 ceramide species, C24:0 dihydroceramide, or total ceramides. Our analysis reveals that specific long‐chain ceramides strongly associate with low cardiovascular fitness in older adults and may be implicated in the pathogenesis of low fitness with aging. Longitudinal studies are needed to further validate these associations and investigate the relationship between ceramides and health outcomes.

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“…Under fasting conditions, sphingomyelin is the most abundant serum sphingolipid, representing 88% of ceramides and sphingolipids, and circulates bound predominately to HDL 2 (12). Serum sphingomyelin has been reported to increase or decrease in the postprandial state (12,34), whereas serum ceramides (C14:0 -20:0) increase, preferentially carried by circulating LDL (12). Observed changes from the fasted to fed state represent the effect of dietary fats to stimulate the de novo pathway for ceramide synthesis (12).…”

Section: Discussionmentioning

confidence: 99%

Serum sphingolipids: relationships to insulin sensitivity and changes with exercise in humans

Bergman

Brozinick

Strauss

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

126

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Ceramides and sphingolipids are a family of lipid molecules that circulate in serum and accumulate in skeletal muscle, promoting insulin resistance. Plasma ceramide and dihydroceramide are related to insulin resistance, yet less is known regarding other ceramide and sphingolipid species. Despite its association with insulin sensitivity, chronic endurance exercise training does not change plasma ceramide and sphingolipid content, with little known regarding a single bout of exercise. We measured basal relationships and the effect of acute exercise (1.5 h at 50% V O2 max) and recovery on serum ceramide and sphingolipid content in sedentary obese individuals, endurancetrained athletes, and individuals with type 2 diabetes (T2D). Basal serum C18:0, C20:0, and C24:1 ceramide and C18:0 and total dihydroceramide were significantly higher in T2D and, along with C16:0 ceramide and C18:0 sphingomyelin, correlated positively with insulin resistance. Acute exercise significantly increased serum ceramide, glucosylceramide, and GM3 gangliosides, which largely decreased to basal values in recovery. Sphingosine 1-phosphate and sphingomyelin did not change during exercise but decreased below basal values in recovery. Serum C16:0 and C18:0 ceramide and C18:0 sphingomyelin, but not the total concentrations of either of them, were positively correlated with markers of muscle NF-B activation, suggesting that specific species activate intracellular inflammation. Interestingly, a subset of sphingomyelin species, notably C14:0, C22:3, and C24:4 species, was positively associated with insulin secretion and glucose tolerance. Together, these data show that unique ceramide and sphingolipid species associate with either protective or deleterious features for diabetes and could provide novel therapeutic targets for the future. insulin sensitivity; athlete's paradox; lipid composition; plasma biomarkers THE GLOBAL BURDEN OF DIABETES continues to rise, fueled by the even greater epidemic of prediabetes (9). Nevertheless, not all of those with prediabetes will develop diabetes (27), highlighting the need to identify nonglycemic markers of disease progression that may also prove useful as new targets for the treatment of diabetes itself. Advances in lipidomics have provided new tools to investigate processes that govern the development of diabetes and its complications beyond that of glucose itself. Serum ceramides, a family of sphingolipids involved in diverse and relevant metabolic processes, have received considerable attention in relation to diabetes, making them prime candidates for further examination. Unlike other biomarkers, discrete serum ceramide profiles are rendered across the spectrum of diabetogenesis, creating speculation that ceramides not only mark but contribute to the disease process (8, 17).Much of this speculation is derived from data generated from in vitro and animal experimentation. Human data to date are limited largely to associations between serum ceramide concentration and risk for both diabetes (15) and related comp...

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Blood sphingolipidomics in healthy humans: impact of sample collection methodology

Cited by 279 publications

References 56 publications

Demographic and clinical variables affecting mid‐ to late‐life trajectories of plasma ceramide and dihydroceramide species

Demographic and clinical variables affecting mid‐ to late‐life trajectories of plasma ceramide and dihydroceramide species

Circulating ceramides are inversely associated with cardiorespiratory fitness in participants aged 54–96 years from the Baltimore Longitudinal Study of Aging

Serum sphingolipids: relationships to insulin sensitivity and changes with exercise in humans

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