Nervonic Acid Abstracts 1

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Nervonic acid in red blood cell sphingomyelin in premature infants: an index of myelin maturation
            (Babin et al., 1993) Download
The present study addresses the question whether nervonic acid (24:1n-9) accumulation in sphingomyelin (SM) of red blood cells (RBC) could yield information on cerebrum maturation in premature infants. The study included 28 premature eutrophic infants of 31.5 wk gestational age. Eleven were fed with human milk, nine with a regular formula and eight with an alpha-linolenate-enriched formula. The fatty acid composition of the SM fraction was determined by gas-liquid chromatography on a 50-m fused silica capillary column. At 32 wk gestational age, the main fatty acids in SM were 16:0, 18:0, 20:0, 22:0, 24:0 and 24:1n-9. After five weeks of feeding, at week 37 of postconceptional age, the most striking variation was a rise in 24:1n-9, from 9.9 +/- 0.7 to 12.8 +/- 0.9 (P < 0.02), regardless of regimen in all three feeding groups. The rise in 24:1n-9 after birth in premature eutrophic infants is the beginning of a trend toward the higher levels in 24:1n-9 observed in mature newborns and older infants. The 24:1n-9 level in SM of RBC from premature infants may reflect 24:1n-9 levels in SM of brain and could thus reflect brain maturity.

Circulating sphingolipid biomarkers in models of type 1 diabetes.
            (Fox et al., 2011) Download
Alterations in lipid metabolism may contribute to diabetic complications. Sphingolipids are essential components of cell membranes and have essential roles in homeostasis and in the initiation and progression of disease. However, the role of sphingolipids in type 1 diabetes remains largely unexplored. Therefore, we sought to quantify sphingolipid metabolites by LC-MS/MS from two animal models of type 1 diabetes (streptozotocin-induced diabetic rats and Ins2(Akita) diabetic mice) to identify putative therapeutic targets and biomarkers. The results reveal that sphingosine-1-phosphate (So1P) is elevated in both diabetic models in comparison to respective control animals. In addition, diabetic animals demonstrated reductions in plasma levels of omega-9 24:1 (nervonic acid)-containing ceramide, sphingomyelin, and cerebrosides. Reduction of 24:1-esterfied sphingolipids was also observed in liver and heart. Nutritional stress via a high-fat diet also reduced 24:1 content in the plasma and liver of mice, exacerbating the decrease in some cases where diabetes was also present. Subcutaneous insulin corrected both circulating So1P and 24:1 levels in the murine diabetic model. Thus, changes in circulating sphingolipids, as evidenced by an increase in bioactive So1P and a reduction in cardio- and neuro-protective omega-9 esterified sphingolipids, may serve as biomarkers for type 1 diabetes and represent novel therapeutic targets.

Effects of Maternal Ω-3 Supplementation on Fatty Acids and on Visual and Cognitive Development.
            (Hurtado et al., 2015)  Download
OBJECTIVES:  The aim of the present study was to elucidate whether a dairy drink enriched with ω-3 long-chain polyunsaturated fatty acid (LC-PUFA) could have an impact on the lipid profile of the mother and the newborn, and also whether this intervention could affect the newborns' visual and cognitive development. METHODS:  A total of 110 pregnant women were randomly assigned to one of the following intervention groups: control group (n = 54), taking 400 mL/day of the control dairy drink, and supplemented group (fish oil [FO]) (n = 56), taking 400 mL/day of the fish oil-enriched dairy drink (including ∼400 mg eicosapentaenoic acid-docosahexaenoic acid [DHA]/day). During the study, the mothers' diets were supervised by a nutritionist to encourage compliance with present recommendations of FA intake. Blood fatty acid profiles were determined in the mother's (at enrollment, at delivery, and at 2.5 and 4 months) and newborn (at delivery and at 2.5 months) placenta and breast milk (colostrum and at 1, 2, and 4 months). Pattern reversal visual evoked potentials (VEPs) (at 2.5 and 7.5 months) and Bayley test (at 12 months) were recorded. RESULTS:  DHA percentage was higher in plasma, erythrocyte membranes, and breast milk samples from the FO group. The ratio of nervonic acid was also higher in plasma and erythrocyte lipids of the mother and newborn's blood samples from the FO group. No differences were observed in the Bayley test. No differences were observed in VEPs between both groups. We observed a shorter latency, however, in the lower visual angle (7.5') in the boys of the supplemented group. CONCLUSIONS:  Omega-3 LC-PUFA dietary supplement during pregnancy and lactation influenced the mother and newborn's fatty acid profile and nervonic acid content but did not show effects on visual and cognitive/psychomotor development.

Plasma Nervonic Acid Is a Potential Biomarker for Major Depressive Disorder: A Pilot Study.
            (Kageyama et al., 2018) Download
Background:  Diagnostic biomarkers of major depressive disorder, bipolar disorder, and schizophrenia are urgently needed, because none are currently available. Methods:  We performed a comprehensive metabolome analysis of plasma samples from drug-free patients with major depressive disorder (n=9), bipolar disorder (n=6), schizophrenia (n=17), and matched healthy controls (n=19) (cohort 1) using liquid chromatography time-of-flight mass spectrometry. A significant effect of diagnosis was found for 2 metabolites: nervonic acid and cortisone, with nervonic acid being the most significantly altered. The reproducibility of the results and effects of psychotropic medication on nervonic acid were verified in cohort 2, an independent sample set of medicated patients [major depressive disorder (n=45), bipolar disorder (n=71), schizophrenia (n=115)], and controls (n=90) using gas chromatography time-of-flight mass spectrometry. Results:  The increased levels of nervonic acid in patients with major depressive disorder compared with controls and patients with bipolar disorder in cohort 1 were replicated in the independent sample set (cohort 2). In cohort 2, plasma nervonic acid levels were also increased in the patients with major depressive disorder compared with the patients with schizophrenia. In cohort 2, nervonic acid levels were increased in the depressive state in patients with major depressive disorder compared with the levels in the remission state in patients with major depressive disorder and the depressive state in patients with bipolar disorder. Conclusion:  These results suggested that plasma nervonic acid is a good candidate biomarker for the depressive state of major depressive disorder.

Lipid biomarkers of lens aging.
            (Mohanty et al., 2013) Download
Lipids are important structural components of cell membranes and have profound effect on membrane fluidity. Lipid profiling and lipidomics have captured increased attention due to the well-recognized roles of lipids in numerous human diseases. Investigating lipid profiles not only provides insights into the specific roles of lipid molecular species in health and diseases, but can also help in identifying potential preventive or therapeutic biomarkers. Cataract, the loss of transparency of eye lens, is a disease of protein aggregation. There are several factors contributing to the stability in protein conformation. Age-related changes in lipid composition could be a contributing factor for altered protein-lipid interaction leading to protein aggregation and cataract. Keeping this in view, in the present study, fatty acid profiling from different age groups of lenses was carried out, using a freshwater catfish as the model. Total lipids were extracted from lenses of three different age groups of fishes (young, adult, and aged) and fatty acid methyl esters (FAME) were prepared and FAME analysis was carried out using gas chromatography-mass spectrometry. The results showed that three fatty acids viz. heneicosylic acid (C21), docosahexaenoic acid (C22:6), nervonic acid (C24:1) which were not present in the adult lens, appeared in the aged lens. On the other hand, eicosenoic acid (C20:1) present in the adult lens was found to be absent in the aged lens. The appearance or disappearance of these fatty acids can possibly serve as biomarkers of aging lens which is the most vulnerable stage for cataract development.


 

Relationships between serum unsaturated fatty acids and coronary risk factors: negative relations between nervonic acid and obesity-related risk factors.
            (Oda et al., 2005) Download
Relative increases in unsaturated fatty acids (USFA) in the diet are considered to exert beneficial effects on coronary risk factors (CRF). However, detailed analysis of the relationships between serum USFA and CRF are scanty and there is no report of the relationship between nervonic acid (NA) and CRF. The objective of the present study was to analyze the relationships between serum USFA and CRF. Body height and weight, blood pressure, fasting serum total cholesterol (TC), triacyl-glycerol (TG), HDL cholesterol (HDLc), fasting blood sugar (FBS), total fatty acid composition, leptin, and high-sensitivity C-reactive protein (CRP) were measured in 31 men (age, 41-78 years) and 11 women (age, 54-77 years). The relationships between serum USFA, and body mass index (BMI), leptin, systolic blood pressure (SBP), diastolic blood pressure (DBP), TC, TG, HDLc, FBS, and CRP were analyzed using multiple regression analysis. The final results were summarized using coronary risk factor scores (CRFS) in order to assess the correlations between USFA with CRF. Oleic acid (OA), linoleic acid (LA), and eicosapentaenoic acid (EPA) were positively related to coronary risk factors (total CRFS = 2, 3, and 4, respectively), while nervonic acid (NA) exerted negative effects on these risk factors (total CRFS = -6 ). It is concluded NA may have preventive effects on obesity-related metabolic disorders.

Differential levels of long chain polyunsaturated fatty acids in women with preeclampsia delivering male and female babies.
            (Roy et al., 2014) Download
Maternal long chain polyunsaturated fatty acids (LCPUFA) play a key role in fetal growth and development. This study for the first time examines the maternal and cord LCPUFA levels in preeclamptic mothers delivering male and female infants. In this study 122 normotensive control pregnant women (gestation≥37 weeks) and 90 women with preeclampsia were recruited. Results indicate lower maternal plasma docosahexaenoic acid (DHA) levels (p<0.05) in women with preeclampsia delivering male babies as compared to normotensive control women delivering male babies. Similarly, cord nervonic acid levels were lower (p<0.01) in women with preeclampsia delivering male babies as compared to normotensive control group. However, cord nervonic acid levels were comparable in women with preeclampsia and normotensive control women delivering female babies. This data suggests that male babies born to mothers with preeclampsia may be at an increased risk of developing neurodevelopmental disorders as compared to female babies. Future studies need to follow up both male and female children born to mothers with preeclampsia since altered levels of LCPUFA at birth may have differential implications for the growth and development.


Localization of nervonic acid beta-oxidation in human and rodent peroxisomes: impaired oxidation in Zellweger syndrome and X-linked adrenoleukodystrophy.
            (Sandhir et al., 1998) Download
Studies with purified subcellular organelles from rat liver indicate that nervonic acid (C24:1) is beta-oxidized preferentially in peroxisomes. Lack of effect by etomoxir, inhibitor of mitochondrial beta-oxidation, on beta-oxidation of lignoceric acid (C24:0), a peroxisomal function, and that of nervonic acid (24:1) compared to the inhibition of palmitic acid (16:0) oxidation, a mitochondrial function, supports the conclusion that nervonic acid is oxidized in peroxisomes. Moreover, the oxidation of nervonic and lignoceric acids was deficient in fibroblasts from patients with defects in peroxisomal beta-oxidation [Zellweger syndrome (ZS) and X-linked adrenoleukodystrophy (X-ALD)]. Similar to lignoceric acid, the activation and beta-oxidation of nervonic acid was deficient in peroxisomes isolated from X-ALD fibroblasts. Transfection of X-ALD fibroblasts with human cDNA encoding for ALDP (X-ALD gene product) restored the oxidation of both nervonic and lignoceric acids, demonstrating that the same molecular defect may be responsible for the abnormality in the oxidation of nervonic as well as lignoceric acid. Moreover, immunoprecipitation of activities for acyl-CoA ligase for both lignoceric acid and nervonic acid indicate that saturated and monoenoic very long chain (VLC) fatty acids may be activated by the same enzyme. These results clearly demonstrate that similar to saturated VLC fatty acids (e.g., lignoceric acid), VLC monounsaturated fatty acids (e.g., nervonic acid) are oxidized preferentially in peroxisomes and that this activity is impaired in X-ALD. In view of the fact that the oxidation of unsaturated VLC fatty acids is defective in X-ALD patients, the efficacy of dietary monoene therapy, "Lorenzo's oil," in X-ALD needs to be evaluated.

Nervonic acid and demyelinating disease.
            (Sargent et al., 1994) Download
Demyelination in adrenoleukodystrophy (ALD) is associated with an accumulation of very long chain saturated fatty acids such as 26:0 stemming from a genetic defect in the peroxisomal beta oxidation system responsible for the chain shortening of these fatty acids. Long chain monoenoic acids such as erucic acid, 22:1(n-9), can normalise elevated serum levels of 26:0 in ALD by depressing their biosynthesis from shorter chain saturated fatty acids. Sphingolipids from post mortem ALD brain have decreased levels of nervonic acid, 24:1(n-9), and increased levels of stearic acid, 18:0. Increased levels of 26:0 are accompanied by decreased nervonic acid biosynthesis in skin fibroblasts from ALD patients. Sphingolipids from post mortem MS brain have the same decreased 24:1(n-9) and increased 18:0 seen in post mortem ALD brain. The 24:1(n-9) content of sphingomyelin is depressed in erythrocytes from multiple sclerosis (MS) patients. Defects in the microsomal biosynthesis of very long chain fatty acids including 24:1(n-9) in 'jumpy' and 'quaking' mice are accompanied by impaired myelination. An impairment in the provision of nervonic acid in demyelinating diseases is indicated, suggesting that dietary therapy with oils rich in very long chain monenoic acid fatty acids may be beneficial in such conditions.

Plasma fatty acids in chronic kidney disease: nervonic acid predicts mortality.
            (Shearer et al., 2012) Download
Although the value of red blood cell fatty acids (FAs) in estimating risk for acute coronary syndrome in the general population is evident, the value of FAs in chronic kidney disease (CKD) is unknown. Here, we provide a pilot analysis in a spectrum of CKD patients. Plasma samples were obtained from 20 incident dialysis patients (CKD stage 5), matched with samples from 10 CKD stage 3-4 patients, and 10 control subjects. Whole plasma FAs were measured using gas chromatography. Whereas neither linoleic acid nor arachidonate acid were altered in CKD, metabolic intermediates of arachidonate synthesis (γ-linolenate and dihomo γ-linolenate) were reduced in CKD. Demming (orthogonal) correlation of FA abundance with estimated GFR identified several saturated and unsaturated FAs in addition to the intermediates; again, neither linoleate nor arachidonate were related. Follow-up data within the CKD stage 5 patients revealed that nervonic acid, a component of membrane sphingolipids and phosphatidylethanolamines, was a significant predictor of all-cause mortality; the age-adjusted relative risk for a 0.15% change is 2.1 (1.4, 3.7; 95% CI; P = .0008). These findings support the exploration of FAs in larger studies for validation of the role FAs in cardiovascular risk and mortality in CKD.

Proportion of nervonic acid in serum lipids is associated with serum plasmalogen levels and metabolic syndrome.
            (Yamazaki et al., 2014) Download
An increase in serum plasmalogens (1-O-alk-1-enyl-2-acyl glycerophospholipids), which are endogenous anti-oxidative phospholipids, can potentially prevent age-related diseases such as atherosclerosis and metabolic syndrome (MetS). Very long chain fatty acids (VLCFAs) in plasma may supply the materials for plasmalogen biosynthesis through peroxisomal beta-oxidation. On the other hand, elevated levels of saturated and monounsaturated VLCFAs in plasma appear to be associated with decreased peroxisomal function, and are a symptom of age-related diseases. To reconcile these contradictory findings, we attempted to investigate the relationship between the serum levels of saturated and monounsaturated VLCFAs, clinical and biochemical parameters, and serum levels of plasmalogens in subjects with MetS (n = 117), who were asymptomatic Japanese males over 40 years of age. Fatty acids in serum lipids were quantified using gas chromatography/mass spectrometry (GC/MS). Serum plasmalogen levels were determined by liquid chromatography using radioactive iodine (¹²⁵I-HPLC), and the molecular composition of serum plasmalogens was analyzed by liquid chromatography-tandem mass spectrometry (LC/MS/MS). We found that MetS subjects showed a significant reduction in the proportion of specific saturated and monounsaturated VLCFAs such as behenic acid (C22:0), lignoceric acid (C24:0), and nervonic acid (C24:1) in serum lipids compared to non-MetS subjects. These VLCFAs were positively associated with serum levels of high density lipoprotein cholesterol (HDL-C) as well as plasmalogen-related parameters, and inversely with serum levels of triglyceride (TG) and small dense low density lipoprotein cholesterol (sdLDL-C). In conclusion, the proportion of nervonic acid in serum lipids is associated with serum levels of plasmalogens and with MetS, and probably reflects the peroxisomal dysfunction and enhancement of endoplasmic reticulum (ER) stress seen in common age-related diseases.

 


References

Babin, F, et al. (1993), ‘Nervonic acid in red blood cell sphingomyelin in premature infants: an index of myelin maturation’, Lipids, 28 (7), 627-30. PubMed: 8355591
Fox, TE, et al. (2011), ‘Circulating sphingolipid biomarkers in models of type 1 diabetes.’, J Lipid Res, 52 (3), 509-17. PubMed: 21068007
Hurtado, JA, et al. (2015), ‘Effects of Maternal Ω-3 Supplementation on Fatty Acids and on Visual and Cognitive Development.’, J Pediatr Gastroenterol Nutr, 61 (4), 472-80. PubMed: 25988553
Kageyama, Y, et al. (2018), ‘Plasma Nervonic Acid Is a Potential Biomarker for Major Depressive Disorder: A Pilot Study.’, Int J Neuropsychopharmacol, 21 (3), 207-15. PubMed: 29040586
Mohanty, BP, et al. (2013), ‘Lipid biomarkers of lens aging.’, Appl Biochem Biotechnol, 169 (1), 192-200. PubMed: 23179275
Oda, E, et al. (2005), ‘Relationships between serum unsaturated fatty acids and coronary risk factors: negative relations between nervonic acid and obesity-related risk factors.’, Int Heart J, 46 (6), 975-85. PubMed: 16394593
Roy, S, et al. (2014), ‘Differential levels of long chain polyunsaturated fatty acids in women with preeclampsia delivering male and female babies.’, Prostaglandins Leukot Essent Fatty Acids, 91 (5), 227-32. PubMed: 25172358
Sandhir, R, et al. (1998), ‘Localization of nervonic acid beta-oxidation in human and rodent peroxisomes: impaired oxidation in Zellweger syndrome and X-linked adrenoleukodystrophy.’, J Lipid Res, 39 (11), 2161-71. PubMed: 9799802
Sargent, JR, K Coupland, and R Wilson (1994), ‘Nervonic acid and demyelinating disease.’, Med Hypotheses, 42 (4), 237-42. PubMed: 8072429
Shearer, GC, et al. (2012), ‘Plasma fatty acids in chronic kidney disease: nervonic acid predicts mortality.’, J Ren Nutr, 22 (2), 277-83. PubMed: 21775161
Yamazaki, Y, et al. (2014), ‘Proportion of nervonic acid in serum lipids is associated with serum plasmalogen levels and metabolic syndrome.’, J Oleo Sci, 63 (5), 527-37. PubMed: 24770479