Very Long Chain Saturated Fatty Acids Research Articles

Abstract P414: Biomarkers of Very Long-chain Saturated Fatty Acids and Incident Coronary Heart Disease: Prospective Evidence From 15 Cohorts in the Fatty Acids and Outcomes Research Consortium

Background: Biomarker levels of very long-chain saturated fatty acids (VLCSFAs) have been found to be favorably associated with cardiovascular risk factors including lower risk of diabetes and reduced triglycerides. Few studies have examined the association between VLCSFAs and coronary heart disease (CHD). Aims: To assess the association of circulating arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) with incident total, fatal, and nonfatal CHD. Methods: We used data from the Fatty Acids and Outcomes Research Consortium consisting of 15 prospective cohorts worldwide which included adults (age≥18 years) who were free of cardiovascular disease and had blood measurements of 20:0, 22:0, and 24:0 at baseline. A study protocol with standardized definitions of exposures, disease outcomes, and covariates was developed, for which each cohort conducted individual participant-level analysis. Cohort-specific associations were pooled using inverse variance-weighted meta-analysis to calculate the overall relative risk (RR) per interquintile range (difference between the 90 th and 10 th percentiles) and 95% confidence interval (CI). Results: Among 33,083 participants, 6,165 cases of total CHD were ascertained. The overall pooled RR and 95% CI were 0.96 (0.89, 1.02) for 20:0, 1.01 (0.92, 1.11) for 22:0, 0.94 (0.86, 1.02) for 24:0, and 0.96 (0.89, 1.04) for 20:0 + 22:0 + 24:0 ( Figure 1 ). However, we noted heterogeneity by lipid compartments, with significant inverse associations for higher 22:0 [0.77 (0.62, 0.96)], 24:0 [0.61 (0.49, 0.77)], and 20:0 + 22:0 + 24:0 [0.73 (0.60, 0.89)] in the total plasma/serum compartment but not in the phospholipid compartment. Similar associations were observed for fatal and nonfatal CHD and when using a random-effects model. Conclusion: Higher circulating VLCSFAs were not associated with total CHD in a global consortium of prospective studies. The finding of an inverse association with total CHD for VLCSFAs in the total plasma/serum compartment warrants further research.

Abstract P492: Circulating Sphingolipids and Risk of Mortality: The Cardiovascular Health Study

Introduction: Recent studies suggest that the type of saturated fatty acid bound to sphingolipids influences sphingolipid activity, and that associations of ceramides (Cer) and sphingomyelins (SM) with cardiovascular outcomes may differ by lipid species. The purpose of this study was to assess associations of Cer and SM species with mortality among 4,612 older adults from the Cardiovascular Health Study, a population-based prospective study of adults aged ≥65 y who were followed from 1992-2015. Hypothesis: Higher levels of circulating Cer and SM with palmitic acid (Cer-16) are associated with a higher risk of mortality (i.e., deaths from cardiovascular disease (CVD) and non-cardiovascular causes) while higher levels of Cer and SM with very-long chain saturated fatty acids arachidic acid (Cer-20 and SM-20), behenic acid (Cer-22 and SM-22), and lignoceric acid (Cer-24 and SM-24) are associated with a lower risk. Methods: The associations of each sphingolipid with mortality were assessed using Cox proportional hazards models. Models adjusted for age, sex, self-reported race, geographic area, education, smoking, alcohol use, BMI, activities of daily living, HDL and LDL cholesterol, triglycerides, systolic blood pressure, physical activity, use of hypertension or lipid-lowering drugs, self-reported health status, prevalent diabetes, CVD, heart failure (HF), and other sphingolipids species. Results: During a median follow-up of 10.2 years (range 0-23 years), 4,099 deaths occurred. At each time, higher levels of Cer-16 and SM-16 were associated with a higher risk of mortality, while higher levels of Cer-22, Cer-24, SM-20, SM-22, and SM-24 were associated with a lower risk of mortality (Figure). Models that did not adjust for diabetes, CVD, and HF produced similar results. Conclusions: These findings suggest that the associations of Cer and SM with the risk of death differ according to the length of their acylated saturated fatty acid, and support the need for future studies to explore mechanisms underlying these relations.

Designer Oils: A Stride for Future

One of the biggest challenges in agricultural sector is to boost up production systems, along with the development of genetically sound crops to get an efficient and sustainable agricultural produce, generating new seed quality traits, especially in oilseed crops. Present review aimed on the alteration of oilseed crops to improve their nutritional composition and industrial utility. Such modifications will include production of high palmitic acid, stearic acid, oleic acid, omega-3 longchain polyunsaturated fatty acids (LC-PUFAs), arachidonic acid, eicosapentaenoic acid, ricinoleic acid, unusual monoenoic fatty acids, reduction in erucic acid and very long chain saturated fatty acids (VLSFA). Manipulation of triacylglycerol structure is another area included in this review so as to enhance the nutritional value of ‘designer’ oils. The focus is also laid on to how new technological interventions, such as synthetic biology, next-generation sequencing, LC-MS/MS targeted lipid analysis, clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) technique and lipidomics are mediating in the development of desired traits in transgenic oilseeds. Transgenic oilseeds producing novel fatty acids will be a better source for providing renewable raw materials that may compete with and eventually replace other nonrenewable sources.

Novel Cellular Functions of Very Long Chain-Fatty Acids: Insight From ELOVL4 Mutations.

Elongation of Very Long chain fatty acids-4 (ELOVL4) protein is a member of the ELOVL family of fatty acid elongases that is collectively responsible for catalyzing formation of long chain fatty acids. ELOVL4 is the only family member that catalyzes production of Very Long Chain Saturated Fatty Acids (VLC-SFA) and Very Long Chain Polyunsaturated Fatty Acids (VLC-PUFA) with chain lengths ≥28 carbons. ELOVL4 and its VLC-SFA and VLC-PUFA products are emerging as important regulators of synaptic signaling and neuronal survival in the central nervous system (CNS). Distinct sets of mutations in ELOVL4 cause three different neurological diseases in humans. Heterozygous inheritance of one set of autosomal dominant ELOVL4 mutations that leads to truncation of the ELOVL4 protein causes Stargardt-like macular dystrophy (STGD3), an aggressive juvenile-onset retinal degeneration. Heterozygous inheritance of a different set of autosomal dominant ELOVL4 mutations that leads to a full-length protein with single amino acid substitutions causes spinocerebellar ataxia 34 (SCA34), a late-onset neurodegenerative disease characterized by gait ataxia and cerebellar atrophy. Homozygous inheritance of a different set of ELOVL4 mutations causes a more severe disease with infantile onset characterized by seizures, spasticity, intellectual disability, ichthyosis, and premature death. ELOVL4 is expressed widely in the CNS and is found primarily in neurons. ELOVL4 is expressed in cell-specific patterns within different regions of the CNS that are likely to be related to disease symptoms. In the retina, ELOVL4 is expressed exclusively in photoreceptors and produces VLC-PUFA that are incorporated into phosphatidylcholine and enriched in the light sensitive membrane disks of the photoreceptor outer segments. VLC-PUFA are enzymatically converted into “elovanoid” compounds that appear to provide paracrine signals that promote photoreceptor and neuronal survival. In the brain, the main ELOVL4 products are VLC-SFA that are incorporated into sphingolipids and enriched in synaptic vesicles, where they regulate kinetics of presynaptic neurotransmitter release. Understanding the function of ELOVL4 and its VLC-SFA and VLC-PUFA products will advance our understanding of basic mechanisms in neural signaling and has potential for developing novel therapies for seizure and neurodegenerative diseases.

Associations of circulating very-long-chain saturated fatty acids and incident type 2 diabetes: a pooled analysis of prospective cohort studies

Saturated fatty acids (SFAs) of different chain lengths have unique metabolic and biological effects, and a small number of recent studies suggest that higher circulating concentrations of the very-long-chain SFAs (VLSFAs) arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) are associated with a lower risk of diabetes. Confirmation of these findings in a large and diverse population is needed. We investigated the associations of circulating VLSFAs 20:0, 22:0, and 24:0 with incident type 2 diabetes in prospective studies. Twelve studies that are part of the Fatty Acids and Outcomes Research Consortium participated in the analysis. Using Cox or logistic regression within studies and an inverse-variance-weighted meta-analysis across studies, we examined the associations of VLSFAs 20:0, 22:0, and 24:0 with incident diabetes among 51,431 participants. There were 14,276 cases of incident diabetes across participating studies. Higher circulating concentrations of 20:0, 22:0, and 24:0 were each associated with a lower risk of incident diabetes. Pooling across cohorts, the RR (95% CI) for incident diabetes comparing the 90th percentile to the 10th percentile was 0.78 (0.70, 0.87) for 20:0, 0.84 (0.77, 0.91) for 22:0, and 0.75 (0.69, 0.83) for 24:0 after adjustment for demographic, lifestyle, adiposity, and other health factors. Results were fully attenuated in exploratory models that adjusted for circulating 16:0 and triglycerides. Results from this pooled analysis indicate that higher concentrations of circulating VLSFAs 20:0, 22:0, and 24:0 are each associated with a lower risk of diabetes.

Circulating Very Long-Chain Saturated Fatty Acids and Heart Failure: The Cardiovascular Health Study.

BackgroundCirculating very‐long‐chain saturated fatty acids (VLSFAs) are integrated biomarkers of diet and metabolism that may point to new risk pathways and potential targets for heart failure (HF) prevention. The associations of VLSFA to HF in humans are not known.Methods and ResultsUsing a cohort study design, we studied the associations of serially measured plasma phospholipid VLSFA with incident HF in the Cardiovascular Health Study. We investigated the associations of time‐varying levels of the 3 major circulating VLSFAs, lignoceric acid (24:0), behenic acid (22:0), and arachidic acid (20:0), with the risk of incident HF using Cox regression. During 45030 person‐years among 4249 participants, we identified 1304 cases of incident HF, including 489 with preserved and 310 with reduced ejection fraction. Adjusting for major HF risk factors and other circulating fatty acids, higher levels of each VLSFAs were associated with lower risk of incident HF (P trend≤0.0007 each). The hazard ratio comparing the highest quintile to the lowest quintile was 0.67 (95% confidence interval, 0.55–0.81) for 24:0, 0.72 (95% confidence interval, 0.60–0.87) for 22:0 and 0.72 (95% confidence interval, 0.59–0.88) for 20:0. The associations were similar in subgroups defined by sex, age, body mass index, coronary heart disease, and diabetes mellitus. Among those with ejection fraction data, the associations appeared similar for those with preserved and with reduced ejection fraction.ConclusionsHigher levels of circulating VLSFAs are associated with lower risk of incident HF in older adults. These novel associations should prompt further research on the role of VLSFA in HF, including relevant new risk pathways.Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT00005133.

Sex-Dimorphic Association of Plasma Fatty Acids with Cardiovascular Fitness in Young and Middle-Aged General Adults: Subsamples from NHANES 2003⁻2004.

To explore the potential association of plasma fatty acids (FAs) and cardiovascular fitness level (CVFL), data of 449 subjects from 2003–2004 National Health and Nutrition Examination Survey (NHANES) were analyzed. Among these 249 men and 200 women, aged 20–50 years (33.4 ± 8.4 year, mean ± Standard Deviation), 79 low, 166 moderate and 204 high CVFL were categorized by age- and gender- specific percentile, respectively. Twenty-four fatty acids were quantified from fasting plasma. Higher levels of 2 very long-chain saturated FAs (VLSFAs): Arachidic acid (AR1, C20:0) and Docosanoic acid (DA1, C22:0) as well as 2 n-6 polyunsaturated FAs (PUFAs): Arachidonic acid (AA, C20:4n-6) and Docosatetraenoic acid (DTA, C22:4n-6) were observed in the subjects with low CVFL. Notably this association exists only in men. Estimated maximal oxygen consumption (VO2max), the marker for cardiorespiratory fitness, was used for further regression analysis. After the adjustment of potential confounding factors (age, smoking, hypertension status, body mass index (BMI), insulin resistance status, and C-reactive protein (CRP), AA was the only FA correlated with low VO2max in women; while in men AR1, DA1, AA, and DTA remain negatively associated with VO2max. This preliminary analysis suggests a sex-dimorphic relationship between these plasma VLSFAs and n-6 PUFAs with CVFL and merits further investigation.

Abstract P044: Plasma Phospholipid Very Long Chain Saturated Fatty Acids and Healthy Aging in Older Adults: The Cardiovascular Health Study

Introduction: Circulating very long-chain saturated fatty acids (VLSFA) are biomarkers of diet and metabolism which impart different biological activities to sphingolipids and may influence physiological pathways relevant to aging. Higher levels of circulating VLSFAs have been associated with lower risk of all-cause mortality, cardiovascular outcomes, and diabetes. Apart from these associations, it is unknown whether these biomarkers are related to the maintenance of healthy aging. Hypothesis: Higher levels of circulating VLSFA are associated with lower risk of unhealthy aging. Methods: Phospholipid fatty acids were measured in serial plasma samples collected among participants of the Cardiovascular Health Study (CHS) in 1992-93, 1998-99, and 2005-06. Incident unhealthy aging was defined as the onset of cardiovascular disease (CVD), cancer, lung disease, severe chronic kidney disease, ≥1 difficulties with activities of daily living (ADL), or reduced cognitive function (Mini-Mental State Examination<80). We assessed the associations of arachidic acid (20:0), behenic acid (22:0) and lignoceric acid (24:0), with risk of incident unhealthy aging using Cox regression with time-updated fatty acid levels and covariates. Results: Among 2,183 CHS participants with one or more fatty acid measure and healthy aging up to the time of their first VLSFA measurement, mean age at baseline was 75 years, 62% were female, and 12% were black. During median follow-up of 8 years, all but 198 participants failed to age successfully. The most common conditions marking the first occurrence of unhealthy aging were ADL difficulties and CVD (27% each). In analyses adjusted for major risk factors, higher levels of 22:0 and 24:0 were associated with lower risk of unhealthy aging (Table). Conclusions: Higher levels of two circulating VLSFA, 22:0 and 24:0, are associated with lower risk of unhealthy aging. These findings open a new avenue of research into these saturated fatty acids and their possible beneficial role in promoting better aging.

Differential effects of saturated fatty acids on the risk of metabolic syndrome: a matched case-control and meta-analysis study

BackgroundWe investigated the association between plasma saturated fatty acids (SFAs) and the risk of metabolic syndrome among ethnic Chinese adults in Taiwan who attended a health check-up center. MethodsA case-control study based on 1000 cases of metabolic syndrome and 1:1 matched control participants (mean age, 54.9 ± 10.7 y; 36% females) were recruited. Metabolic syndrome was defined according to the criteria of the International Diabetes Federation. Gas chromatography was used to measure the distribution of fatty acids in plasma (% of total fatty acids). ResultsEven-chain SFAs, including 14:0, 16:0, and 18:0, were associated with metabolic syndrome; the adjusted odds ratio [OR] and 95% confidence interval [CI] per standard deviation [SD] difference was 3.32, [1.98–5.59]; however, very-long-chain SFAs, including 20:0, 21:0, 22:0, 23:0, and 24:0, were inversely associated with metabolic syndrome. The adjusted OR [95% CI] per SD difference was 0.67 [0.58–0.78]. The area under the receiver operative characteristic curve increased from 0.814 in the basic model to 0.815 (p = 0.54, compared with the basic model), 0.818 (p < 0.0001), and 0.820 (p < 0.0001) after adding odd-chain, even-chain, and very-long chain SFAs. A meta-analysis based on 12 studies showed that the summarized OR for type 2 diabetes mellitus was 1.16 [0.96–1.41] for the top versus bottom SFAs. ConclusionsDifferent carbon numbers of SFAs have been shown to have differential effects on the status of metabolic syndrome, implying that SFAs are not homogenous for the effects.

Elongation of very Long-Chain (>C24) Fatty Acids in Clarias gariepinus: Cloning, Functional Characterization and Tissue Expression of elovl4 Elongases

Elongation of very long-chain fatty acid 4 (Elovl4) proteins participate in the biosynthesis of very long-chain (>C24) saturated and polyunsaturated fatty acids (FA). Previous studies have shown that fish possess two different forms of Elovl4, termed Elovl4a and Elovl4b. The present study aimed to characterize both molecularly and functionally two elovl4 cDNA from the African catfish Clarias gariepinus. The results confirmed that C. gariepinus possessed two elovl4-like elongases with high homology to two previously characterized Elovl4 from Danio rerio, and thus they were termed accordingly as Elovl4a and Elovl4b. The C. gariepinus Elovl4a and Elovl4b have open reading frames (ORF) of 945 and 915 base pairs, respectively, encoding putative proteins of 314 and 304 amino acids, respectively. Functional characterization in yeast showed both Elovl4 enzymes have activity towards all the PUFA substrates assayed (18:4n-3, 18:3n-6, 20:5n-3, 20:4n-6, 22:5n-3, 22:4n-6 and 22:6n-3), producing elongated products of up to C36. Moreover, the C. gariepinus Elovl4a and Elovl4b were able to elongate very long-chain saturated FA (VLC-SFA) as denoted by increased levels of 28:0 and longer FA in yeast transformed with elovl4 ORF compared to control yeast. These results confirmed that C. gariepinus Elovl4 play important roles in the biosynthesis of very long-chain FA. Tissue distribution analysis of elovl4 mRNAs showed both genes were widely expressed in all tissues analyzed, with high expression of elovl4a in pituitary and brain, whereas female gonad and pituitary had the highest expression levels for elovl4b.

Abstract MP014: Very Long Chain Saturated Fatty Acids and Diabetes Risk: Meta-Analysis of Cohort Studies in the FORCE Consortium

Background: Circulating saturated fatty acids are biomarkers of diet and metabolism that may influence the pathogenesis of diabetes. Unlike palmitic acid (16:0), which has been extensively studied, little is known of the relationship of very long-chain saturated fatty acids (VLSFAs), with 20 carbons or more, to diabetes risk. Objective: To investigate the associations of circulating levels of VLSFA with incident diabetes. Methods: A meta-analysis was conducted within a consortium of prospective (cohort or nested case-control) studies having circulating measures of one or more VLSFAs, including arachidic acid (20:0), behenic acid (22:0) and lignoceric acid (24:0). Standardized analysis was conducted in each study using pre-specified models, exposures, outcomes, and covariates. Study-specific estimates were pooled using fixed effects meta-analysis. Results: Current findings were based on 9 participating studies, including 46,549 total participants and 13,750 incident diabetes. In multivariable-adjusted analyses, higher levels of all 3 VLSFAs were associated with lower risk of incident diabetes. Pooled RRs (95% CI) per interquintile range were 0.80 (0.71-0.90) for 20:0; 0.83 (0.76-0.91) for 22:0; and 0.70 (0.63-0.79) for 24:0, after adjustment for demographics, lifestyle factors and clinical conditions. Additional adjustments for circulating palmitic acid and triglyceride levels moved the RRs toward the null (illustrated for 24:0, in model 3 of the Figure ). Conclusions: Based on meta-analysis of results from several studies around the world, biomarker levels of VLSFA are associated with lower risk of incident diabetes, potentially mediated by effects on circulating triglycerides and 16:0.

Abstract 11369: Circulating Very Long-Chain Saturated Fatty Acids and Heart Failure

Introduction: Myocardial fibrosis with apoptosis contributes to heart failure (HF), and ceramides, with their role in apoptosis, may contribute to this pathophysiological process. However, experimental studies show that ceramides carrying a VLSFA are in fact protective against apoptosis, providing strong evidence that very long-chain saturated fatty acids (VLSFA) impart different biological activity to ceramides. Hypothesis: Circulating VLSFA are associated with lower risk of HF. Methods: We addressed this hypothesis in the Cardiovascular Health Study (CHS), a prospective study of older adults (mean age 72 at entry) with repeated measures of plasma phospholipid fatty acids. Circulating fatty acids were measured at the study baseline in 1992-93, and again where possible, in the 6 th year and 13 th year of follow-up, in plasma phospholipids. We assessed the associations of three VLSFA, arachidic acid (20:0), behenic acid (22:0) and lignoceric acid (24:0), with risk of incident HF using Cox regression with time-dependent covariates and fatty acids. Results: The analyses included 4,060 CHS participants with fatty acid data at least at one time point. During 43,430 person-years, we identified 1228 incident HF. In analyses adjusted for age, sex, race, center, blood pressure, BMI, waist circumference, physical activity, smoking, history of coronary heart disease, atrial fibrillation, diabetes, and current use of antihypertensive medications, higher levels of 22:0 and 24:0 were associated with lower risk of incident HF (Table). With further adjustment for fatty acids previously found to be associated with HF, all three VLSFA were associated with lower risk of incident HF. Conclusions: Higher levels of circulating VLSFA are associated with lower risk of incident HF. These novel findings may open a new avenue of research into these little studied saturated fatty acids and their possible beneficial role in preventing HF.

Effect of Saturated Very Long-Chain Fatty Acids on the Organization of Lipid Membranes: A Study Combining (2)H NMR Spectroscopy and Molecular Dynamics Simulations.

Little is known about the interaction of very long-chain saturated fatty acids (VLCFAs) with biological membranes. However, this could play an important role on interleaflet interactions and signal transduction mechanisms in cells. The aim of this work is to determine how VLCFA structurally adapts in fluid phospholipid bilayers, since both species must exhibit a significant hydrophobic mismatch. The membrane organization has been described by means of (2)H NMR and molecular dynamics simulations. Our results show that the protonation state affects the position and order of free fatty acids (FFAs) in phospholipid membranes. It was shown that the protonated FFA-C24 carboxyl group is located slightly under the POPC head group and therefore its acyl chain can interact with the lipids of the opposite leaflet. This interdigitation of the end of the acyl chain causes a second plateau observed in SC-D profiles, a very unusual feature in lipid systems.

Current Progress in Deciphering Importance of VLC-PUFA in the Retina.

Stargardt-like macular dystrophy-3 (STGD3) is a juvenile-onset disease caused by mutations in ELOVL4 (elongation of very long fatty acids-4). This gene product catalyzes the elongation of long chain saturated and polyunsaturated fatty acids (LC-FAs and LC-PUFAs) into very long chain FAs and PUFAs (VLC-FAs and VLC-PUFAs). These mutations cause a frame shift in the ELOVL4 transcript, introducing a premature stop codon that results in the translation of a truncated protein that has lost a C-terminus endoplasmic reticulum (ER) retention/retrieval signal. The truncated protein is not targeted to the ER, the site of very long-chain PUFA (VLC-PUFA; 28-40 carbons) synthesis. Expression of the ELOVL4 gene is limited mainly to the brain, testis, skin, and photoreceptor cells of the retina. While the skin and brain contain very long chain saturated fatty acids (VLC-FAs), the other tissues expressing ELOVL4 contain VLC-PUFAs, with sperm and the retina having the highest levels. This review focuses on the current information available concerning the role of VLC-PUFAs in the retina.

Circulating Very-Long-Chain Saturated Fatty Acids and Incident Coronary Heart Disease in US Men and Women.

Circulating very-long-chain saturated fatty acids (VLCSFAs) may play an active role in the origin of cardiometabolic diseases. We measured 3 VLCSFAs (C20:0, C22:0, and C24:0) in plasma and erythrocytes using gas-liquid chromatography among 794 incident coronary heart disease (CHD) cases who were prospectively identified and confirmed among women in the Nurses' Health Study (NHS; 1990-2006) and among men in the Health Professionals Follow-Up Study (HPFS; 1994-2008). A total of 1233 CHD-free controls were randomly selected and matched to cases in these 2 cohorts. Conditional logistic regression was used to estimate hazard ratios and 95% confidence intervals. Plasma VLCSFAs were correlated with favorable profiles of blood lipids, C-reactive protein, and adiponectin in the NHS and HPFS and with fasting insulin and C-peptide levels in a nationally representative US comparison population. After multivariate adjustment for lifestyle factors, body mass index, diet, and long-chain n-3 and trans fatty acids, total VLCSFAs in plasma were associated with a 52% decreased risk of CHD (pooled hazard ratio, 0.48; 95% confidence interval, 0.32-0.72, comparing extreme quintiles; Ptrend<0.0001). For VLCSFAs in erythrocytes, a nonsignificant inverse trend with CHD risk was observed (pooled hazard ratio, 0.66; 95% confidence interval, 0.41-1.06, comparing extreme quintiles; Ptrend=0.16). In US men and women, plasma VLCSFAs were independently associated with favorable profiles of blood lipids and other cardiovascular disease risk markers and a lower risk of CHD. Erythrocyte VLCSFAs were associated with nonsignificant trends of lower CHD risk. Future studies are warranted to elucidate the underlying biological mechanisms.

Plasma phospholipid very-long-chain saturated fatty acids and incident diabetes in older adults: the Cardiovascular Health Study

Circulating saturated fatty acids (SFAs) are integrated biomarkers of diet and metabolism that may influence the pathogenesis of diabetes. In epidemiologic studies, circulating levels of palmitic acid (16:0) are associated with diabetes; however, very-long-chain SFAs (VLSFAs), with 20 or more carbons, differ from palmitic acid in their biological activities, and little is known of the association of circulating VLSFA with diabetes. By using data from the Cardiovascular Health Study, we examined the associations of plasma phospholipid VLSFA levels measured at baseline with subsequent incident diabetes. A total of 3179 older adults, with a mean age of 75 y at study baseline (1992-1993), were followed through 2011. We used multiple proportional hazards regression to examine the associations of arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) with diabetes. Baseline levels of each VLSFA were cross-sectionally associated with lower triglyceride levels and lower circulating palmitic acid. We identified 284 incident diabetes cases during follow-up. Compared with the lowest quartile, levels of arachidic acid in the highest quartile of the fatty acid distribution were associated with a 47% lower risk of diabetes (95% CI: 23%, 63%; P-trend: <0.001), after adjustment for demographics, lifestyle factors, and clinical conditions. In analogous comparisons, levels of behenic and lignoceric acid were similarly associated with 33% (95% CI: 6%, 53%; P-trend: 0.02) and 37% (95% CI: 11%, 55%; P-trend: 0.01) lower diabetes risk, respectively. Adjustment for triglycerides and palmitic acid attenuated the associations toward the null, and only the association of arachidic acid remained statistically significant (32% lower risk for fourth vs. first quartile; P-trend: 0.04). These results suggest that circulating VLSFAs are associated with a lower risk of diabetes, and these associations may be mediated by lower triglycerides and palmitic acid. The study highlights the need to distinguish the effects of different SFAs and to explore determinants of circulating VLSFAs. This trial was registered at clinicaltrials.gov as NCT00005133.

Dietary Very Long Chain Saturated Fatty Acids and Metabolic Factors: Findings from the Korea National Health and Nutrition Examination Survey 2013.

The present study was aim to evaluate the association between very long chain saturated fatty acids (VLSFAs) and metabolic syndrome (MetS) in Korean population. The study population were recruited from the Korea National Health and Nutrition Examination Survey VI (2013). Using the cross-sectional study design, socio-demographic factors, medical history, and clinical measurements were investigated according to quartiles of VLSFAs intake. The associations between each and sum of VLSFAs intake and MetS were assessed by logistic regression. The result indicated that higher intake of VLSFAs was significantly associated with favorable metabolic status, including lower levels of circulating triglyceride (TG) (p < 0.05). Additionally, subjects with higher intake of arachidic acid and total VLSFAs were negatively associated with MetS risk compared to subjects with lower intake of those fatty acids (p < 0.05). In conclusion, dietary VLSFAs intake was associated with metabolic risk factors and lower risk of MetS in Korean population.

Genetic loci associated with circulating levels of very long-chain saturated fatty acids

Very long-chain saturated fatty acids (VLSFAs) are saturated fatty acids with 20 or more carbons. In contrast to the more abundant saturated fatty acids, such as palmitic acid, there is growing evidence that circulating VLSFAs may have beneficial biological properties. Whether genetic factors influence circulating levels of VLSFAs is not known. We investigated the association of common genetic variation with plasma phospholipid/erythrocyte levels of three VLSFAs by performing genome-wide association studies in seven population-based cohorts comprising 10,129 subjects of European ancestry. We observed associations of circulating VLSFA concentrations with common variants in two genes, serine palmitoyl-transferase long-chain base subunit 3 (SPTLC3), a gene involved in the rate-limiting step of de novo sphingolipid synthesis, and ceramide synthase 4 (CERS4). The SPTLC3 variant at rs680379 was associated with higher arachidic acid (20:0 , P = 5.81 × 10−13). The CERS4 variant at rs2100944 was associated with higher levels of 20:0 (P = 2.65 × 10−40) and in analyses that adjusted for 20:0, with lower levels of behenic acid (P = 4.22 × 10−26) and lignoceric acid (P = 3.20 × 10−21). These novel associations suggest an inter-relationship of circulating VLSFAs and sphingolipid synthesis.

Erythrocyte very long-chain saturated fatty Acids associated with lower risk of incident sudden cardiac arrest

Prior studies suggest that circulating n-3 and trans-fatty acids influence the risk of sudden cardiac arrest (SCA). Yet, while other fatty acids also differ in their membrane properties and biological activities which may influence SCA, little is known about the associations of other circulating fatty acids with SCA. The aim of this study was to investigate the associations of 17 erythrocyte membrane fatty acids with SCA risk. We used data from a population-based case-control study of SCA in the greater Seattle, Washington, area. Cases, aged 25–74 years, were out-of-hospital SCA patients, attended by paramedics (n=265). Controls, matched to cases by age, sex and calendar year, were randomly identified from the community (n=415). All participants were free of prior clinically-diagnosed heart disease. Blood was obtained at the time of cardiac arrest by attending paramedics (cases) or at the time of an interview (controls). Higher levels of erythrocyte very long-chain saturated fatty acids (VLSFA) were associated with lower risk of SCA. After adjustment for risk factors and levels of n-3 and trans-fatty acids, higher levels of 20:0 corresponding to 1 SD were associated with 30% lower SCA risk (13–43%, p=0.001). Higher levels of 22:0 and 24:0 were associated with similar lower SCA risk (ORs for 1 SD-difference: 0.71 [95% CI: 0.57–0.88, p=0.002] for 22:0; and 0.79 [95% CI: 0.63–0.98, p=0.04] for 24:0). These novel findings support the need for investigation of biologic effects of circulating VLSFA and their determinants.

X-linked adrenoleukodystrophy: Diagnostic and follow-up system in Japan

X-linked adrenoleukodystrophy (ALD) is an intractable neurodegenerative disease associated with the accumulation of very long-chain saturated fatty acids (VLCFA) in tissues and body fluids. We have established a Japanese referral center for the diagnosis of ALD, using VLCFA measurements and mutation analysis of the ABCD1 gene, and have identified 60 kinds of mutations in 69 Japanese ALD families, which included 38 missense mutations, 6 nonsense mutations, 8 frame-shift mutations, 3 amino acid deletions, 2 exon-skip mutations and 3 large deletions. A total of 24 kinds of mutations (40%) were identified only in Japanese patients by referring to the current worldwide ALD mutation database. There was no clear correlation between these mutations and phenotypes of 81 male patients in these 69 families. About 12% of the individuals with ALD had de novo mutations by mutation analysis in the male probands and their mothers, which should be helpful data for genetic counseling. The only effective therapy for the cerebral form of ALD should be hematopoietic stem cell transplantation at the early stages of the cerebral symptoms, therefore, we performed presymptomatic diagnosis of ALD by extended familial screening of the probands with careful genetic counseling, and established a long follow-up system for these patients to prevent the progression of brain involvement and to monitor the adrenocortical insufficiency. Further elucidation of pathology in ALD, especially concerning the mechanisms of the onset of brain involvement, is expected.