Genetic association between FADS and ELOVL polymorphisms and the circulating levels of EPA/DHA in humans: a scoping review.

BACKGROUND: Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are two omega-3 fatty acids that can be synthesized out of their precursor alpha-linolenic acid (ALA). FADS and ELOVL genes encode the desaturase and elongase enzymes required for EPA and DHA synthesis from ALA; however, single nucleotide polymorphisms (SNPs) in FADS and ELOVL genes could modify the levels of EPA and DHA synthesized from ALA although there is no consensus in this area. This review aims to investigate EPA and DHA circulating levels in human blood and their association with FADS or ELOVL. METHODS: PubMed, Cochrane, and Scopus databases were used to identify research articles. They were subsequently reviewed by two independent investigators. RESULTS: Initially, 353 papers were identified. After removing duplicates and articles not meeting inclusion criteria, 98 full text papers were screened. Finally, this review included 40 studies investigating FADS and/or ELOVL polymorphisms. A total of 47 different SNPs in FADS genes were reported. FADS1 rs174537, rs174547, rs174556 and rs174561 were the most studied SNPs, with minor allele carriers having lower levels of EPA and DHA. SNPs in the FADS genes were in high linkage disequilibrium. SNPs in FADS were correlated with levels of EPA and DHA. No conclusion could be drawn with the ELOVL polymorphisms since the number of studies was too low. CONCLUSION: Specific SNPs in FADS gene, such as rs174537, have strong associations with circulating levels of EPA and DHA. Continued investigation regarding the impact of genetic variants related to EPA and DHA synthesis is warranted.

A vegetable fat-based diet delays psychomotor and cognitive development compared with maternal dairy fat intake in infant gray mouse lemurs.

Dairy fat has a unique lipid profile; it is rich in short- and medium-chain saturated fatty acids that induce ketone production and has a balanced ω6/ω3 ratio that promotes cognitive development in early life. Moreover, the high consumption of vegetable oils in pregnant and lactating women raises concerns regarding the quality of lipids provided to offspring. Here, we investigate maternal dairy fat intake during gestation and lactation in a highly valuable primate model for infant nutritional studies, the gray mouse lemur (Microcebus murinus). Two experimental diets are provided to gestant mouse lemurs: a dairy fat-based (DF) or vegetable fat-based diet (VF). The psychomotor performance of neonates is tested during their first 30 days. Across all tasks, we observe more successful neonates born to mothers fed a DF diet. A greater rate of falls is observed in 8-day-old VF neonates, which is associated with delayed psychomotor development. Our findings suggest the potential benefits of lipids originating from a lactovegetarian diet compared with those originating from a vegan diet for the psychomotor development of neonates.

Sex, Body Mass Index, and APOE4 Increase Plasma Phospholipid-Eicosapentaenoic Acid Response During an ω-3 Fatty Acid Supplementation: A Secondary Analysis.

BACKGROUND: The brain is concentrated with omega (ω)-3 (n-3) fatty acids (FAs), and these FAs must come from the plasma pool. The 2 main ω-3 FAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), must be in the form of nonesterified fatty acid (NEFA) or esterified within phospholipids (PLs) to reach the brain. We hypothesized that the plasma concentrations of these ω-3 FAs can be modulated by sex, body mass index (BMI, kg/m2), age, and the presence of the apolipoprotein (APO) E-ε4 allele in response to the supplementation. OBJECTIVES: This secondary analysis aimed to determine the concentration of EPA and DHA within plasma PL and in the NEFA form after an ω-3 FA or a placebo supplementation and to investigate whether the factors change the response to the supplement. METHODS: A randomized, double-blind, placebo-controlled trial was conducted. Participants were randomly assigned to either an ω-3 FA supplement (DHA 0.8 g and EPA 1.7 g daily) or to a placebo for 6 mo. FAs from fasting plasma samples were extracted and subsequently separated into PLs with esterified FAs and NEFAs using solid-phase extraction. DHA and EPA concentrations in plasma PLs and as NEFAs were quantified using gas chromatography. RESULTS: EPA and DHA concentrations in the NEFA pool significantly increased by 31%-71% and 42%-82%, respectively, after 1 and 6 mo of ω-3 FA supplementation. No factors influenced plasma DHA and EPA responses in the NEFA pool. In the plasma PL pool, DHA increased by 83%-109% and EPA by 387%-463% after 1 and 6 mo of ω-3 FA supplementation. APOE4 carriers, females, and individuals with a BMI of ≤25 had higher EPA concentrations than noncarriers, males, and those with a BMI of >25, respectively. CONCLUSIONS: The concentration of EPA in plasma PLs are modulated by APOE4, sex, and BMI. These factors should be considered when designing clinical trials involving ω-3 FA supplementation. This trial was registered at clinicaltrials.gov as NCT01625195.

Decoupling of mRNA and Protein Expression in Aging Brains Reveals the Age-Dependent Adaptation of Specific Gene Subsets.

During aging, changes in gene expression are associated with a decline in physical and cognitive abilities. Here, we investigate the connection between changes in mRNA and protein expression in the brain by comparing the transcriptome and proteome of the mouse cortex during aging. Our transcriptomic analysis revealed that aging mainly triggers gene activation in the cortex. We showed that an increase in mRNA expression correlates with protein expression, specifically in the anterior cingulate cortex, where we also observed an increase in cortical thickness during aging. Genes exhibiting an aging-dependent increase of mRNA and protein levels are involved in sensory perception and immune functions. Our proteomic analysis also identified changes in protein abundance in the aging cortex and highlighted a subset of proteins that were differentially enriched but exhibited stable mRNA levels during aging, implying the contribution of aging-related post- transcriptional and post-translational mechanisms. These specific genes were associated with general biological processes such as translation, ribosome assembly and protein degradation, and also important brain functions related to neuroplasticity. By decoupling mRNA and protein expression, we have thus characterized distinct subsets of genes that differentially adjust to cellular aging in the cerebral cortex.

Investigating the plasma-liver-brain axis of omega-3 fatty acid metabolism in mouse knock-in for the human apolipoprotein E epsilon 4 allele.

The metabolism of docosahexaenoic acid (DHA), an omega-3 fatty acid, is different in carriers of APOE4, the main genetic risk factor for late-onset Alzheimer's disease. The brain relies on the plasma DHA pool for its need, but the plasma-liver-brain axis in relation to cognition remains obscure. We hypothesized that this relationship is compromised in APOE4 mice considering the differences in fatty acid metabolism between APOE3 and APOE4 mice. Male and female APOE3 and APOE4 mice were fed either a diet enriched with DHA (0.7 g DHA/100 g diet) or a control diet for 8 months. There was a significant genotype × diet interaction for DHA concentration in the liver and adipose tissue. In the cortex, a genotype effect was found where APOE4 mice had a higher concentration of DHA than APOE3 mice fed the control diet. There was a significant genotype × diet interaction for the liver and hippocampal arachidonic acid (AA). APOE4 mice had 20-30% lower plasma DHA and AA concentrations than APOE3 mice, independent of diet. Plasma and liver DHA levels were significantly correlated in APOE3 and APOE4 mice. In APOE4 mice, there was a significant correlation between plasma, adipose tissues, cortex DHA and the Barnes maze and/or with a better recognition index. Moreover, higher AA levels in the liver and the hippocampus of APOE4 mice were correlated with lower cognitive performance. Our results suggest that there is a plasma-liver-brain axis of DHA that is modified in APOE4 mice. Moreover, our data support that APOE4 mice rely more on plasma DHA than APOE3 mice, especially in cognitive performance. Any disturbance in plasma DHA metabolism might have a greater impact on cognition in APOE4 carriers.

Comparative Pharmacokinetic of Curcuminoids Formulations with an Omega-3 Fatty Acids Monoglyceride Carrier: A Randomized Cross-Over Triple-Blind Study.

There is a growing interest for curcuminoids in the general population and the scientific research community. Curcuminoids, derived from turmeric spice, are lipophiles and therefore have a low solubility in water which hence have a low bioavailability in the human plasma. To circumvent this issue, a natural product developed by Biodroga Nutraceuticals combined curcuminoids with omega-3 fatty acids (OM3) esterified in monoglycerides (MAG). The objective was to perform a 24 h pharmacokinetics in humans receiving a single dose of curcuminoid formulated by three different means, and to compare their plasma curcuminoids concentration. Sixteen males and fifteen females tested three formulations: 400 mg of curcuminoids powder extract, 400 mg of curcuminoids in rice oil and 400 mg of curcuminoids with 1 g MAG-OM3. Blood samples were collected at 0, 1, 2, 3, 4, 5, 6, 8, 10 and 24 h post dose intake. Plasma samples were analyzed by ultra high-performance liquid chromatography with a triple quadrupole mass spectrometer (UPLC-MS/MS). Twenty-four hours after a single dose intake, the total plasma curcuminoids area under the curve (AUC) reached 166.8 ± 17.8 ng/mL*h, 134.0 ± 12.7 ng/mL*h and 163.1 ± 15.3 ng/mL*h when curcuminoids were provided with MAG-OM3, with rice oil or in powder, respectively. The Cmax of total curcuminoids reached between 11.9-17.7 ng/mL at around 4 h (Tmax). One-hour post-dose, the curcuminoids plasma concentration was 40% higher in participants consuming the MAG-OM3 compared to the other formulations. Thus, in a young population, plasma curcuminoids 24 h pharmacokinetics and its increase shortly after the single dose intake were higher when provided with MAG-OM3 than rice oil.

The Influence of Family History of Type 2 Diabetes on Metabolism during Submaximal Aerobic Exercise and in the Recovery Period in Postmenopausal Women.

Aging and family history of type 2 diabetes (T2D) are known risk factors of T2D. Younger first-degree relatives (FDR) of T2D patients have shown early metabolic alterations, which could limit exercise's ability to prevent T2D. Thus, the objective was to determine whether exercise metabolism was altered during submaximal exercise in FDR postmenopausal women. Nineteen inactive postmenopausal women (control: 10, FDR: 9) aged 60 to 75 years old underwent an incremental test on a cycle ergometer with intensity ranging from 40 to 70% of peak power output. Participants consumed 50 mg of 13C-palmitate 2 h before the test. At the end of each stage, glucose, lactate, glycerol, non-esterified fatty acids and 13C-palmitate were measured in plasma, and 13CO2 was measured in breath samples. Gas exchanges and heart rate were both monitored continuously. There were no between-group differences in substrate oxidation, plasma substrate concentrations or 13C recovered in plasma or breath. Interestingly, despite exercising at a similar relative intensity to control, FDR were consistently at a lower percentage of heart rate reserve. Overall, substrate plasma concentration and oxidation are not affected by family history of T2D in postmenopausal women and therefore not a participating mechanism in the altered response to exercise previously reported. More studies are required to better understand the mechanisms involved in this response.

Alteration of Fatty Acid Profile in Fragile X Syndrome.

Fragile X Syndrome (FXS) is the most prevalent monogenic cause of Autism Spectrum Disorders (ASDs). Despite a common genetic etiology, the affected individuals display heterogenous metabolic abnormalities including hypocholesterolemia. Although changes in the metabolism of fatty acids (FAs) have been reported in various neuropsychiatric disorders, it has not been explored in humans with FXS. In this study, we investigated the FA profiles of two different groups: (1) an Argentinian group, including FXS individuals and age- and sex-matched controls, and (2) a French-Canadian group, including FXS individuals and their age- and sex-matched controls. Since phospholipid FAs are an indicator of medium-term diet and endogenous metabolism, we quantified the FA profile in plasma phospholipids using gas chromatography. Our results showed significantly lower levels in various plasma FAs including saturated, monosaturated, ω-6 polyunsaturated, and ω-3 polyunsaturated FAs in FXS individuals compared to the controls. A decrease in the EPA/ALA (eicosapentaenoic acid/alpha linoleic acid) ratio and an increase in the DPA/EPA (docosapentaenoic acid/eicosapentaenoic acid) ratio suggest an alteration associated with desaturase and elongase activity, respectively. We conclude that FXS individuals present an abnormal profile of FAs, specifically FAs belonging to the ω-3 family, that might open new avenues of treatment to improve core symptoms of the disorder.