Polyunsaturated Fatty Acid Metabolism Research Articles

Gene Expression Analysis of Potato (Solanum tuberosum L.) Lipoxygenase Cascade and Oxylipin Signature under Abiotic Stress.

The metabolism of polyunsaturated fatty acids through the lipoxygenase-catalyzed step and subsequent reactions is referred to as the lipoxygenase (LOX) pathway. The components of this system, such as jasmonates, are involved in growth, development and defense reactions of plants. In this report, we focus on dynamics of expression of different LOX pathway genes and activities of target enzymes with three abiotic stress factors: darkness, salinity and herbicide toxicity. To obtain a more complete picture, the expression profiles of marker genes for salicylic acid, abscisic acid, ethylene, auxin and gibberellin-dependent signaling systems under the same stresses were also analyzed. The gene expression in Solanum tuberosum plants was analyzed using qRT-PCR, and we found that the LOX-cascade-related genes responded to darkness, salinity and herbicide toxicity in different ways. We detected activation of a number of 9-LOX pathway genes; however, in contrast to studies associated with biotic stress (infection), the 9-divinyl ether synthase branch of the LOX cascade was inhibited under all three stresses. GC-MS analysis of the oxylipin profiles also showed the main activity of the 9-LOX-cascade-related enzymes after treatment with herbicide and darkness.

Liquid chromatography-mass spectrometry method for discovering the metabolic markers to reveal the potential therapeutic effects of naringin on osteoporosis

The pharmacological effects and therapeutic targets of naringin (NG) against osteoporosis (OP) is still unclear. Liquid chromatography quadrupole time-of-flight mass spectrometry (LC-Q-TOF/MS) based non-targeted metabonomics has been used to explore the differentiated metabolites and potential biological pathways of NG in the pathological process of OP. Using network pharmacology analysis, the key protein targets of NG against OP were also screened. By the metabonomics analysis, a total of 33 differentiated metabolites in serum were discovered, of which 21 were significantly regulated by NG treatment. These metabolites majorly associated with to amino acid metabolism,polyunsaturated fatty acid metabolism, pyruvate metabolism and glycerophospholipidmetabolism. Using the network pharmacology prediction analysis, NG was related to the expression changes of 13 important protein targets. It showed that high-throughput metabonomics strategy integrated with network pharmacology could insight into molecular mechanisms of natural products.

Expression of genes and localization of enzymes involved in polyunsaturated fatty acid synthesis in rabbit testis and epididymis

The metabolism of polyunsaturated fatty acids (PUFAs) plays an important role in male reproduction. Linoleic and alpha-linolenic acids need to be provided in the diet and they are converted into long chain polyunsaturated fatty acids by steps of elongation and desaturation, exerted by elongases 2 (ELOVL2) and 5 (ELOVL5) and Δ5- (FADS1) and Δ6-desaturase (FADS2). This study aims to assess the gene expression and localization of enzymes involved in the synthesis of n-3 and n-6 long-chain PUFAs in control rabbits and those fed diets containing 10% extruded flaxseed. Enzyme and PUFA localization were assessed in the testes and epididymis by immunofluorescence. Testes showed high gene expression of FADS2, ELOVL2 and ELOVL5 and low expression of FADS1. Intermediate metabolites, enzymes and final products were differently found in Leydig, Sertoli and germinal cells. FADS2 was localized in interstitial cells and elongated spermatids; ELOVL5 in meiotic cells; FADS1 was evident in interstitial tissue, Sertoli cells and elongated spermatids; ELOVL2 in interstitial cells. Epididymal vesicles were positive for FADS1, ELOVL2 and ELOVL5 as well as docosahexaenoic, eicosapentaenoic, and arachidonic acids. This knowledge of fatty acids (FA) metabolism in spermatogenesis and the influence of diet on FA profile could help identify causes of male infertility, suggesting new personalized therapy.

Metabolomics Signature and Potential Application of Serum Polyunsaturated Fatty Acids Metabolism in Patients With Vitiligo.

Vitiligo is a depigmented skin disorder caused by a variety of factors, including autoimmune, metabolic disturbance or their combined effect, etc. Non-targeted metabolomic analyses have denoted that dysregulated fatty acids metabolic pathways are involved in the pathogenesis of vitiligo. However, the exact category of fatty acids that participate in vitiligo development and how they functionally affect CD8+ T cells remain undefined. We aimed to determine the difference in specific fatty acids among vitiligo patients and healthy individuals and to investigate their association with clinical features in patients with vitiligo. Serum levels of fatty acids in 48 vitiligo patients and 28 healthy individuals were quantified by performing ultra-performance liquid chromatography-tandem mass spectrometry. Univariate and multivariate analyses were carried out to evaluate the significance of differences. Moreover, flow cytometry was used to explore the effect of indicated fatty acids on the function of CD8+ T cells derived from patients with vitiligo. We demonstrated that serological level of alpha-linolenic acid (ALA) was markedly upregulated, while that of arachidonic acid (ARA), arachidic acid (AA) and behenic acid were significantly downregulated in patients with vitiligo. Moreover, ALA levels were positively associated with vitiligo area scoring index (VASI) and ARA was a probable biomarker for vitiligo. We also revealed that supplementation with ARA or nordihydroguaiaretic acid (NDGA) could suppress the function of CD8+ T cells. Our results showed that vitiligo serum has disorder-specific phenotype profiles of fatty acids described by dysregulated metabolism of polyunsaturated fatty acids. Supplementation with ARA or NDGA might promote vitiligo treatment. These findings provide novel insights into vitiligo pathogenesis that might add to therapeutic options.

NAD+ Levels Are Augmented in Aortic Tissue of ApoE-/- Mice by Dietary Omega-3 Fatty Acids.

Maintaining bioenergetic homeostasis provides a means to reduce the risk of cardiovascular events during chronological aging. Nicotinamide adenine dinucleotide (NAD+) acts as a signaling molecule, and its levels were used to govern several biological pathways, for example, promoting angiogenesis by SIRT1 (sirtuin 1)-mediated inhibition of Notch signaling to rejuvenate capillary density of old-aged mice. NAD+ modulation shows promise in the vascular remodeling of endothelial cells. However, NAD+ distribution in atherosclerotic regions remains uncharacterized. Omega-3 polyunsaturated fatty acids consumption, such as docosahexaenoic acid and eicosapentaenoic acid, might increase the abundance of cofactors in blood vessels due to omega-3 polyunsaturated fatty acids metabolism. Apolipoprotein E-deficient (ApoE-/-) mice were fed a Western diet, and the omega-3 polyunsaturated fatty acids-treated groups were supplemented with docosahexaenoic acid (1%, w/w) or eicosapentaenoic acid (1%, w/w) for 3 weeks. Desorption electrospray ionization mass spectrometry imaging was exploited to detect exogenous and endogenous NAD+ imaging. NAD+, NADH, NADP+, NADPH, FAD+, FADH, and nicotinic acid adenine dinucleotide of the aortic arches were detected higher in the omega-3 polyunsaturated fatty acids-treated mice than the nontreated control. Comparing the distribution in the outer and inner layers of the arterial walls, only NADPH was detected slightly higher in the outer part in eicosapentaenoic acid-treated mice. Supplementation of adding docosahexaenoic acid or eicosapentaenoic acid to the Western diet led to a higher NAD+, FAD+, and their metabolites in the aortic arch. Considering the pleiotropic roles of NAD+ in biology, this result serves as a beneficial therapeutic strategy in the animal model counter to pathological conditions.

A Distinct Metabolically Defined Central Nucleus Circuit Bidirectionally Controls Anxiety-Related Behaviors.

Anxiety disorders are debilitating psychiatric diseases that affect ∼16% of the world's population. Although it has been proposed that the central nucleus of the amygdala (CeA) plays a role in anxiety, the molecular and circuit mechanisms through which CeA neurons modulate anxiety-related behaviors are largely uncharacterized. Soluble epoxide hydrolase (sEH) is a key enzyme in the metabolism of polyunsaturated fatty acids (PUFAs), and has been shown to play a role in psychiatric disorders. Here, we reported that sEH was enriched in neurons in the CeA and regulated anxiety-related behaviors in adult male mice. Deletion of sEH in CeA neurons but not astrocytes induced anxiety-like behaviors. Mechanistic studies indicated that sEH was required for maintaining the the excitability of sEH positive neurons (sEHCeA neurons) in the CeA. Using chemogenetic manipulations, we found that sEHCeA neurons bidirectionally regulated anxiety-related behaviors. Notably, we identified that sEHCeA neurons directly projected to the bed nucleus of the stria terminalis (BNST; sEHCeA-BNST). Optogenetic activation and inhibition of the sEHCeA-BNST pathway produced anxiolytic and anxiogenic effects, respectively. In summary, our studies reveal a set of molecular and circuit mechanisms of sEHCeA neurons underlying anxiety.SIGNIFICANCE STATEMENT Soluble epoxide hydrolase (sEH), a key enzyme that catalyzes the degradation of EETs, is shown to play a key role in mood disorders. It is well known that sEH is mostly localized in astrocytes in the prefrontal cortex and regulates depressive-like behaviors. Notably, sEH is also expressed in central nucleus of the amygdala (CeA) neurons. While the CeA has been studied for its role in the regulation of anxiety, the molecular and circuit mechanism is quite complex. In the present study, we explored a previously unknown cellular and circuitry mechanism that guides sEHCeA neurons response to anxiety. Our findings reveal a critical role of sEH in the CeA, sEHCeA neurons and CeA-bed nucleus of the stria terminalis (BNST) pathway in regulation of anxiety-related behaviors.

Exploiting three-dimensional human hepatic constructs to investigate the impact of rs174537 on fatty acid metabolism.

The Modern Western Diet has been associated with the rise in metabolic and inflammatory diseases, including obesity, diabetes, and cardiovascular disease. This has been attributed, in part, to the increase in dietary omega-6 polyunsaturated fatty acid (PUFA) consumption, specifically linoleic acid (LA), arachidonic acid (ARA), and their subsequent metabolism to pro-inflammatory metabolites which may be driving human disease. Conversion of dietary LA to ARA is regulated by genetic variants near and within the fatty acid desaturase (FADS) haplotype block, most notably single nucleotide polymorphism rs174537 is strongly associated with FADS1 activity and expression. This variant and others within high linkage disequilibrium may potentially explain the diversity in both diet and inflammatory mediators that drive chronic inflammatory disease in human populations. Mechanistic exploration into this phenomenon using human hepatocytes is limited by current two-dimensional culture models that poorly replicate in vivo functionality. Therefore, we aimed to develop and characterize a three-dimensional hepatic construct for the study of human PUFA metabolism. Primary human hepatocytes cultured in 3D hydrogels were characterized for their capacity to represent basic lipid processing functions, including lipid esterification, de novo lipogenesis, and cholesterol efflux. They were then exposed to control and LA-enriched media and reproducibly displayed allele-specific metabolic activity of FADS1, based on genotype at rs174537. Hepatocytes derived from individuals homozygous with the minor allele at rs174537 (i.e., TT) displayed the slowest metabolic conversion of LA to ARA and significantly reduced FADS1 and FADS2 expression. These results support the feasibility of using 3D human hepatic cultures for the study of human PUFA and lipid metabolism and relevant gene-diet interactions, thereby enabling future nutrition targets in humans.

To Explore Ideas From the Altered Metabolites: The Metabolomics of Pathological Scar.

Pathological scars are dermal fibroproliferative disorders due to rapid inflammatory response after dermal injury. The altered metabolites could reflect pathophysiological changes directly. However, it has not cleared how the metabolites change scars. To explore new ideas of pathological scars from the altered metabolites by using ultra-performance liquid chromatography coupled to tandem mass spectrometry and identifying the key genes. Keloid (KS, n = 10), hypertrophic scar (HS, n = 10), and normal skin (NS, n = 10) were collected. Ultra-performance liquid chromatography coupled to tandem mass spectrometry was used to identify and characterize metabolites. Differential metabolites were analyzed by orthogonal partial least square discriminant analysis and Student t test. The key pathways were analyzed via Kyoto Encyclopedia of Genes and Genomes, and the related enzymes were verified by real-time Polymerase Chain Reaction, both in tissues and their dermal fibroblasts. Two hundred fourteen metabolites were detected in total, mostly were fatty acids and amino acids. In the KS and NS groups, 65 different metabolites were screened ( P < 0.05), and the polyunsaturated fatty acids (PUFAs) metabolism and butyric acid in keloid should be concerned. The messenger Ribonucleic Acid expression of fatty acid desaturase 1 and fatty acid desaturase 2, which are the key enzyme of PUFA metabolism, were lower in KS and keloid-derived fibroblasts, P < 0.05. In HS group, 17 metabolites were significantly different and branched chain amino acids degradation was the key pathway. Moreover, branched chain keto acid dehydrogenase E1 subunit alpha was lower expressed in HS and their fibroblasts compared with NS, P < 0.05. Polyunsaturated fatty acids and butyric acid may be associated with the generation of keloids. The pathogenesis of hypertrophic scars may be involved in branched chain amino acids degradation, which is worth paying attention to.

Ponicidin suppresses pancreatic cancer growth by inducing ferroptosis: Insight gained by mass spectrometry-based metabolomics

BackgroundPancreatic cancer is one of the most common malignant tumors of the digestive tract. Ponicidin, a tetracyclic diterpenoid active ingredient extracted from the traditional phytomedicine Rubescens, has high safety and great inhibitory effect on the proliferation of a variety of cancer cells, especially malignant tumor cells of the digestive tract. However, the inhibitory effect and mechanism of ponicidin on pancreatic cancer cells is still unclear. Our study aimed to use metabonomics technology to analyze and explore the suppressive effect of ponidicin against pancreatic cancer cells. MethodsMTT and flow cytometry were conducted to study the potential effect of ponicidin on SW1990 cells. Secondly, UPLC-MS/MS was used to analyze the small molecule metabolites and relevant differential metabolic pathways induced by ponicidin treatment. Furthermore, through the determination of glutathione peroxidase 4 (GPX4) activity and molecular docking simulation experiments, the effects of intracellular GPX4 activity and GSH/GSSG ratio after ponicidin were evaluated. Finally, the determination of the content of iron ions and malondialdehyde in cells, and the experiment of the effect of ferroptosis inhibitors on cell viability, the effect of ponicidin on the induction of ferroptosis in SW1990 cells was also detected. ResultsThe IC50 of ponicidin on SW1990 cells was 20 μM, which could significantly induce cell apoptosis and arrest the cells in G2/M phase. Metabolomics results showed that the contents of endogenous small molecules such as gamma-glutamylcysteine, 5-oxoproline, glutamic acid, reduced glutathione (GSH), oxidized glutathione (GSSG) and arachidonic acid have changed significantly. Main differential compounds were involved in the gamma-glutamyl cycle and polyunsaturated fatty acid metabolism of pancreatic cancer cell lines. Additionally, ponicidin could covalently bind to GSH in SW1990 cells to form a conjugate Pon-GSH, which further reduced the content of free GSH and GPX4 activity in cells. Notably, ponicidin dose-dependently increased levels of iron ions, malondialdehyde and reactive oxygen species in SW1990 cells, and the ferroptosis inhibitors could significantly block the effects of ponicidin on the proliferation of SW1990 cells. ConclusionPonicidin could suppress the pancreatic cancer cell proliferation via inducing ferroptosis by inhibiting the gamma-glutamyl cycle and regulating the polyunsaturated fatty acid metabolism in SW1990 cells.

Gut microbes shape microglia and cognitive function during malnutrition.

Fecal‐oral contamination promotes malnutrition pathology. Lasting consequences of early life malnutrition include cognitive impairment, but the underlying pathology and influence of gut microbes remain largely unknown. Here, we utilize an established murine model combining malnutrition and iterative exposure to fecal commensals (MAL‐BG). The MAL‐BG model was analyzed in comparison to malnourished (MAL mice) and healthy (CON mice) controls. Malnourished mice display poor spatial memory and learning plasticity, as well as altered microglia, non‐neuronal CNS cells that regulate neuroimmune responses and brain plasticity. Chronic fecal‐oral exposures shaped microglial morphology and transcriptional profile, promoting phagocytic features in MAL‐BG mice. Unexpectedly, these changes occurred independently from significant cytokine‐induced inflammation or blood–brain barrier (BBB) disruption, key gut‐brain pathways. Metabolomic profiling of the MAL‐BG cortex revealed altered polyunsaturated fatty acid (PUFA) profiles and systemic lipoxidative stress. In contrast, supplementation with an ω3 PUFA/antioxidant‐associated diet (PAO) mitigated cognitive deficits within the MAL‐BG model. These findings provide valued insight into the malnourished gut microbiota‐brain axis, highlighting PUFA metabolism as a potential therapeutic target.

STING orchestrates the crosstalk between polyunsaturated fatty acid metabolism and inflammatory responses

SummaryConcerted alteration of immune and metabolic homeostasis underlies several inflammation-related pathologies, ranging from metabolic syndrome to infectious diseases. Here, we explored the coordination of nucleic acid-dependent inflammatory responses and metabolic homeostasis. We reveal that the STING (stimulator of interferon genes) protein regulates metabolic homeostasis through inhibition of the fatty acid desaturase 2 (FADS2) rate-limiting enzyme in polyunsaturated fatty acid (PUFA) desaturation. STING ablation and agonist-mediated degradation increased FADS2-associated desaturase activity and led to accumulation of PUFA derivatives that drive thermogenesis. STING agonists directly activated FADS2-dependent desaturation, promoting metabolic alterations. PUFAs in turn inhibited STING, thereby regulating antiviral responses and contributing to resolving STING-associated inflammation. Thus, we have unveiled a negative regulatory feedback loop between STING and FADS2 that fine-tunes inflammatory responses. Our results highlight the role of metabolic alterations in human pathologies associated with aberrant STING activation and STING-targeting therapies.

A Bioinformatics Perspective on the Dysregulation of Ferroptosis and Ferroptosis-related Immune Cell Infiltration in Alzheimer's Disease.

Alzheimer's disease (AD) is the most prevalent dementia worldwide, but its pathophysiology and molecular events remain unknown. Herein, we first analyzed the differential expression pattern of patients' AD hippocampus through gene expression array data from the GEO database. Notch2nl, TGFB1I1, and LTF were up-regulated in AD patients, while ARPC1A, CHGB, and MPV17 down-regulated. Second, dysregulation of ferroptosis related genes was demonstrated from our data: PCBP2 and FTL significantly up-significant in AD hippocampus, while VDAC2, LPCAT3, GSS, ACSL4, and ACSL6 significantly down-regulated. The protein-protein interactions (PPI) network revealed that FTL was involved in iron metabolism and utilization, while ACSL4 and ACSL6 were involved in a polyunsaturated fatty acids metabolism network. Gene correlation analysis on differential expressed genes (DEGs) indicated that ferroptosis regulates a series of biological processes and pathways related to AD pathogenesis. Third, ferroptosis-related DEGs regulated the immune cell infiltration pattern in the AD hippocampus, characterized by decreased memory B cells, increased memory resting CD4+ T cells, memory activated CD4+ T cells, and resting NK cells. The altered expression of ferroptosis-related DEGs affected the infiltration of specific immune cell types. The model constructed by the seven ferroptosis-related differential genes may accurately predict the outcome of AD occurrence. Finally, qPCR validation on these ferroptosis-related DEGs in APPswe/PSEN1dE9 mice confirmed the dysregulated expression of Pcbp2, FTL, GSS, and ACSL4 in the AD hippocampus and forebrain. In conclusion, our results supported the conception that the AD brain revealed dysregulated ferroptosis and immune cell infiltration.

Dysregulated lipid metabolism in colorectal cancer.

Lipid metabolism presents a targetable metabolic vulnerability in colorectal cancer (CRC). Lipid signatures and cancer-cell lipid requirements may serve as noninvasive diagnostic and prognostic biomarkers and as a therapeutic target, respectively. A growing body of new studies highlight the complexity of lipid metabolism in CRC. Cancer cells are able to utilize an alternative fatty acid desaturation pathway, underlining the metabolic plasticity of tumors. CRC tissue shows a robust triglyceride-species signature with prognostic value in CRC patients. Lipidomic analyses in germfree and colonized mice identify a unique lipid signature and suggest that bacteria inhibit metabolism of polyunsaturated fatty acids by blocking desaturase and elongase activities. Cellular stress responses, particularly the well characterized unfolded protein response, are involved in regulating lipid synthesis and homeostasis, and contribute to adaptation of the lipid environment. Together, lipid metabolism, the intestinal microbiota and cellular stress responses unarguably play crucial roles in CRC. A number of recent advances in our understanding of dysregulated lipid metabolism in CRC underline the importance of this research field. An improved knowledge of the complex interplay between lipid metabolism, cellular stress and the intestinal microbiota in the context of CRC may lead to novel therapeutic strategies.

Amino Acids and Lipids Associated with Long-Term and Short-Term Red Meat Consumption in the Chinese Population: An Untargeted Metabolomics Study.

Red meat (RM) consumption is correlated with multiple health outcomes. This study aims to identify potential biomarkers of RM consumption in the Chinese population and evaluate their predictive ability. We selected 500 adults who participated in the 2015 China Health and Nutrition Survey and examined their overall metabolome differences by RM consumption by using elastic-net regression, then evaluate the predictivity of a combination of filtered metabolites; 1108 metabolites were detected. In the long-term RM consumption analysis 12,13-DiHOME, androstenediol (3α, 17α) monosulfate 2, and gamma-Glutamyl-2-aminobutyrate were positively associated, 2-naphthol sulfate and S-methylcysteine were negatively associated with long-term high RM consumption, the combination of metabolites prediction model evaluated by area under the receiver operating characteristic curve (AUC) was 70.4% (95% CI: 59.9–80.9%). In the short-term RM consumption analysis, asparagine, 4-hydroxyproline, and 3-hydroxyisobutyrate were positively associated, behenoyl sphingomyelin (d18:1/22:0) was negatively associated with short-term high RM consumption. Combination prediction model AUC was 75.6% (95% CI: 65.5–85.6%). We identified 10 and 11 serum metabolites that differed according to LT and ST RM consumption which mainly involved branch-chained amino acids, arginine and proline, urea cycle and polyunsaturated fatty acid metabolism. These metabolites may become a mediator of some chronic diseases among high RM consumers and provide new evidence for RM biomarkers.

Lipids and brain inflammation in APOE4-associated dementia.

To highlight recent developments in studying mechanisms by which the apolipoprotein E4 (APOE4) allele affects the metabolism of brain lipids and predisposes the brain to inflammation and Alzheimer's disease (AD) dementia. APOE4 activates Ca2+ dependent phospholipase A2 (cPLA2) leading to changes in arachidonic acid (AA), eicosapentaenoic acid and docosahexaenoic acid signaling cascades in the brain. Among these changes, the increased conversion of AA to eicosanoids associates with sustained and unresolved chronic brain inflammation. The effects of APOE4 on the brain differ by age, disease stage, nutritional status and can be uncovered by brain imaging studies of brain fatty acid uptake. Reducing cPLA2 expression in the dementia brain presents a viable strategy that awaits to be tested. Fatty acid brain imaging techniques can clarify how changes to brain polyunsaturated fatty acid metabolism during the various phases of AD and guide the development of small molecules to mitigate brain inflammation.

The effect of APOE4 on plasma and cerebrospinal fluid polyunsaturated fatty acids following DHA supplementation

AbstractBackgroundPast studies indicate that APOE4 promotes a metabolic shift toward greater fatty acid usage. We have shown that APOE4 is associated with lower increase in cerebrospinal fluid (CSF) polyunsaturated fatty acids (PUFAs) following supplementation with triglyceride (TG) based DHA. The purpose of this study is to define the effect of APOE4 on plasma and CSF lipids using a comprehensive lipidomic analysis.MethodPlasma and CSF samples were obtained from the DHA Brain Delivery Pilot, a randomized clinical trial of DHA treatment (n=13) vs placebo (n=13) in non‐demented older participants (CDR ≤ 0.5, age&gt; 55 years old) and stratified by APOE4. Participants were provided 2,040 mg DHA daily in the form of TG‐DHA for six months.ResultFollowing supplementation, levels of phosphatidylcholine DHA (PC 38:6) and cholesterol ester DHA (CE 22:6) had the largest increase in CSF (p&lt;0.0001). Using principal component analysis, changes in plasma TG (56:8), TG (58:10), ePE (40:8), TG (56:9), PC (40:6) and PC (38:6) had the strongest correlations with changes in CSF PC (38:6, p&lt;0.001). Figure 1 shows Pearson correlation coefficients of all plasma and CSF lipids. Among all lipid species, changes in PUFA enriched TGs were significantly correlated between CSF and plasma. APOE4 had a significant effect on CSF TG (52:6) changes, with the mean increase in E4 carriers significantly (0.039 units) less than in E4 non‐carriers (p=0.0072) after adjusting for baseline levels and treatment group.ConclusionOur findings demonstrate the first time the existence of PUFAs within a TG pool in CSF that correlates with the corresponding plasma TG pool, suggesting an exchange of TG particles at the CSF‐blood barrier. The effect of APOE4 on the metabolism of PUFAs is strongest on TG enriched PUFAs and supports their greater oxidation in APOE4. These findings help explain why APOE4 carriers are vulnerable to dietary omega‐3 deficiency, and less responsive to short term omega‐3 supplementation.

Milk fat as a source of bioactive compounds

Milk fat as a source of bioactive compounds

Fatty Acid Metabolism and Derived-Mediators Distinctive of PPAR-α Activation in Obese Subjects Post Bariatric Surgery

Bariatric surger (BS) is characterized by lipid metabolic changes as a response to the massive release of non-esterified fatty acids (NEFA) from adipose depots. The study aimed at evaluating changes in polyunsaturated fatty acids (PUFA) metabolism and biosynthesis of the lipid mediators N-acylethanolamines (NAE), as indices of nuclear peroxisome proliferator-activated receptor (PPAR)-α activation. The observational study was performed on 35 subjects (27 female, 8 male) with obesity, undergoing bariatric surgery. We assessed plasma FA and NAE profiles by LC-MS/MS, clinical parameters and anthropometric measures before and 1 and 6 months after bariatric surgery. One month after bariatric surgery, as body weight and clinical parameters improved significantly, we found higher plasma levels of N-oleoylethanolamine, arachidonic and a 22:6-n3/20:5-n3 ratio as evidence of PPAR-α activation. These changes corresponded to higher circulating levels of NEFA and a steep reduction of the fat mass. After 6 months 22:6-n3/20:5-n3 remained elevated and fat mass was further reduced. Our data suggest that the massive release of NEFA from adipose tissue at 1-Post, possibly by inducing PPAR-α, may enhance FA metabolism contributing to fat depot reduction and improved metabolic parameters in the early stage. However, PUFA metabolic changes favor n6 PUFA biosynthesis, requiring a nutritional strategy aimed at reducing the n6/n3 PUFA ratio.

Omega 3/6 ratios: Usage and epigenetic changes in health and Alzheimer's disease

AbstractBackgroundFrom our previous research, we identified circulating metabolites that are associated with cognitive performance and dementia including polyunsaturated fatty acids (PUFA), in particular plasma levels of Omega‐3. To follow up on this finding, we sought to explore potential mechanism mediating the effect of Omega‐3 and Omega‐6 on these neurodegenerative phenotypes. Herein, we hypothesized that modulation of immune response and inflammation may mediate the effect of PUFA on neurodegenerative diseases.Methods1.Validate our PUFA ratios hypothesis on the MAPT intervention study. 2.Evaluate the epigenetic mechanisms modulation derived from genetics using genome‐wide association studies. 3.Corroborate previous results on real methylation data from the DELCODE study using the EPIC array. 4.Evaluate the biological age derived by epigenetics and its implications in healthy and cognitively affected subjects.ResultsThe effect of the PUFA ratios follows the same trend on the MAPT study as previously described during our first period. We observed that the methylation of the genes coding for key enzymes of PUFA metabolism is modulated by levels of Omega‐3. Likewise, these methylation changes have been described in susceptibility genes for Alzheimer’s disease (AD) that modulate immune response. Finally, methylated signals also enabled the prediction of biological age. We observed that biological age in DELCODE participants differs from chronological age depending on the status of the participants.ConclusionsThe present analysis suggests that PUFA ratios are associated with cognitive decline as we previously described. Moreover, we suggest that genetic signals located in the immune‐related gene cluster MS4A are modulated by changes in DNA methylation. The same epigenetic modulation seems to mediate the genetic effect discovered in the sTREM2 GWAS. Interestingly, methylation modulation in MS4A gene has been previously reported using an independent approach. Likewise, TREM2 locus seems to be affected by methylation changes. Finally, our methylation data allowed us to analyze the biological age of cognitively affected individuals and find some clear differences with their chronological ages. Using our results, we will explore whether PUFA levels, and the ratio built on Omega‐6 and Omega‐3, modulate levels of CSF sTREM2 offering thereby a potential connection between PUFA levels and neuroinflammation in the context of AD.

The assessment of plasma fatty acid profiles in newly diagnosed treatment-naive paediatric Crohn's disease.

Fatty acid (FA) profiles as potentially relevant components of Crohn's disease (CD) have been insufficiently analysed. We sought to explore the plasma profiles of n-3 and n-6 polyunsa-turated fatty acids (PUFAs) in newly diagnosed untreated active CD. We included 26 consecutive CD pediatric patients (<19 years) and 14 healthy controls (HCs). Disease characteristics, including inflammatory markers, dietary histories, and the Pediatric Crohn's Disease Activity Index (PCDAI), were obtained. The profiles of plasma FAs in plasma lipid classes were analysed by gas chromatography with FID detection of methyl esters. The erythrocyte sedimentation rate, C-reactive protein level and fecal calprotectin level (all p<0.001) were significantly higher in CD patients than in HCs. Most changes were observed in plasma phospholipids (PLs), such as a higher content of n-3 and changes in n-6 long-chain PUFAs in the CD group. The CD group had a lower ratio of n-6/n-3 PUFAs in PLs (p<0.001) and triacylglycerols (TAGs) (p<0.01). Correlations of the FA content in plasma PLs with disease activity scores of CD were also observed, which were positive for the sum of monounsaturated fatty acids (MUFAs) as well as oleic acid (18:1n-9) (both p<0.05). The metabolism of PUFAs is significantly altered even in treatment-naive newly diagnosed active pediatric CD, and the content of major FAs in PLs correlates with disease activity and inflammatory markers, thus probably contributing to the still unclear early disease pathogenesis.