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Biomedicine & Pharmacotherapy =... Sep 2022As a primarily N6-methyladenosine methyltransferase, methyltransferase 3 (METTL3) plays a crucial role in nonalcoholic fatty liver disease. However, its regulatory...
BACKGROUND
As a primarily N6-methyladenosine methyltransferase, methyltransferase 3 (METTL3) plays a crucial role in nonalcoholic fatty liver disease. However, its regulatory mechanism in steatosis remains unknown.
METHODS
Alpha mouse liver 12 (AML12) cells were induced by free fatty acids (FFA). Triglycerides, lipid droplet assay, and Oil Red O staining were performed to evaluate steatosis. The expression of METTL3 and cytochrome P450 family 4 subfamily f polypeptide 40 (CYP4F40) was measured using Western blotting, real-time quantitative polymerase chain reaction, and dual-luciferase reporter assay. Triglycerides, total cholesterol, almandine aminotransferase, and aspartate aminotransferase were assayed after cinnamaldehyde treatment. Transcriptomics and metabolomics were performed to determine how METTL3 and cinnamaldehyde regulate steatosis.
RESULTS
METTL3 protein level was reduced in FFA-induced steatosis in AML12 cells, and METTL3 knockdown aggravated the steatosis. Cinnamaldehyde alleviated steatosis by increasing METTL3 expression. A combined transcriptomics and metabolomics analysis revealed that METTL3 knockdown reduced CYP4F40 expression and reduced the level of capric acid, gamma-linolenic acid, arachidonic acid, and docosapentaenoic acid. Cinnamaldehyde promoted CYP4F40 expression by increasing METTL3 and increased the levels of capric acid, gamma-linolenic acid, arachidonic acid, and docosapentaenoic acid. Finally, the beneficial effects of cinnamaldehyde on steatosis were reversed after METTL3 knockdown.
CONCLUSIONS
METTL3 knockdown aggravated steatosis in AML12 cells through CYP4F40-mediated fatty acid metabolism, and cinnamaldehyde alleviated steatosis via the METTL3-CYP4F40 pathway.
Topics: Acrolein; Animals; Arachidonic Acids; Fatty Acids, Nonesterified; Methyltransferases; Mice; Non-alcoholic Fatty Liver Disease; Triglycerides; gamma-Linolenic Acid
PubMed: 35780619
DOI: 10.1016/j.biopha.2022.113367 -
Food Science & Nutrition Jun 2023For ages, indigenous small fish species have been important in food and nutritional security of poor communities in low income countries. Freshwater fish, in particular...
For ages, indigenous small fish species have been important in food and nutritional security of poor communities in low income countries. Freshwater fish, in particular fatty fish species are attracting a great attention because they are good sources of health promoting long chain omega-3 fatty acids. Docosahexaenoic acid (DHA, C22:6-3), Docosapentaenoic acid (DPA, C22:5-3) and eicosapentaenoic acid (EPA, C20:5-3) are the main omega-3 PUFAs known to confer health benefits in humans if consumed in required amounts. While nutritionally valued, omega-3 PUFAs in fish are susceptible to oxidative damage during processing, transportation and subsequent storage. Lake Victoria sardines (), are rich source of chemically unstable omega-3 fatty acids DHA, DPA and EPA. Traditionally, sardines are preserved by sun drying, deep frying and smoking. Sardine products are transported, stored and marketed at ambient temperatures. Generally, uncontrolled and higher temperatures are known to increase vulnerability of polyunsaturated fatty acids to oxidation which in turn results into loss of nutritional and sensory qualities. This study investigated changes of fat acids in sun dried, deep fried and smoked sardines during storage. Lipolysis and the progressive hydroperoxides formation were monitored by free fatty acids (FFAs) and peroxide value (PV) respectively. None volatile secondary products of lipid oxidation were measured by thiobabituric acid reactive substances (TBARS). Fatty acids were analyzed by gas chromatography with a flameionization detector (GC-FID). Deep fried sardines maintained the lowest and apparently stable PV, TBARS and FFAs. Proportions of saturated fatty acids and polyunsaturated fatty acids decreased with time while that of monounsaturated fatty acids increased. Omega-3 fatty acids EPA, DPA and DHA decreased with increase in storage time. In 21 days of storage, DHA was oxidized beyond detectable levels in all sardine products. Gradual increase in FFAs in sun dried sardines was suggestive of lipid hydrolysis induced by enzymes.
PubMed: 37324847
DOI: 10.1002/fsn3.3284 -
Frontiers in Molecular Biosciences 2021Studies of key metabolite variations and their biological mechanisms in cerebral infarction (CI) have increased our understanding of the pathophysiology of the disease....
Studies of key metabolite variations and their biological mechanisms in cerebral infarction (CI) have increased our understanding of the pathophysiology of the disease. However, how metabolite variations in different periods of CI influence these biological processes and whether key metabolites from different periods may better predict disease progression are still unknown. We performed a systematic investigation using the metabonomics method. Various metabolites in different pathways were investigated by serum metabolic profiling of 143 patients diagnosed with CI and 59 healthy controls. Phe-Phe, carnitine C18:1, palmitic acid, cis-8,11,14-eicosatrienoic acid, palmitoleic acid, 1-linoleoyl-rac-glycerol, MAG 18:1, MAG 20:3, phosphoric acid, 5α-dihydrotestosterone, Ca, K, and GGT were the major components in the early period of CI. GCDCA, glycocholate, PC 36:5, LPC 18:2, and PA showed obvious changes in the intermediate time. In contrast, trans-vaccenic acid, linolenic acid, linoleic acid, all-cis-4,7,10,13,16-docosapentaenoic acid, arachidonic acid, DHA, FFA 18:1, FFA 18:2, FFA 18:3, FFA 20:4, FFA 22:6, PC 34:1, PC 36:3, PC 38:4, ALP, and Crea displayed changes in the later time. More importantly, we found that phenylalanine metabolism, medium-chain acylcarnitines, long-chain acylcarnitines, choline, DHEA, LPC 18:0, LPC 18:1, FFA 18:0, FFA 22:4, TG, ALB, IDBIL, and DBIL played vital roles in the development of different periods of CI. Increased phenylacetyl-L-glutamine was detected and may be a biomarker for CI. It was of great significance that we identified key metabolic pathways and risk metabolites in different periods of CI different from those previously reported. Specific data are detailed in the Conclusion section. In addition, we also explored metabolite differences of CI patients complicated with high blood glucose compared with healthy controls. Further work in this area may inform personalized treatment approaches in clinical practice for CI by experimentally elucidating the pathophysiological mechanisms.
PubMed: 35242810
DOI: 10.3389/fmolb.2021.784288 -
Clinical Epigenetics Feb 2024Dietary intake of n-3 polyunsaturated fatty acids (PUFA) may have a protective effect on the development of cardiovascular diseases, diabetes, depression and cancer,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Dietary intake of n-3 polyunsaturated fatty acids (PUFA) may have a protective effect on the development of cardiovascular diseases, diabetes, depression and cancer, while a high intake of n-6 PUFA was often reported to be associated with inflammation-related traits. The effect of PUFAs on health outcomes might be mediated by DNA methylation (DNAm). The aim of our study is to identify the impact of PUFA intake on DNAm in the Cooperative Health Research in the Region of Augsburg (KORA) FF4 cohort and the Leiden Longevity Study (LLS).
RESULTS
DNA methylation levels were measured in whole blood from the population-based KORA FF4 study (N = 1354) and LLS (N = 448), using the Illumina MethylationEPIC BeadChip and Illumina HumanMethylation450 array, respectively. We assessed associations between DNAm and intake of eight and four PUFAs in KORA and LLS, respectively. Where possible, results were meta-analyzed. Below the Bonferroni correction threshold (p < 7.17 × 10), we identified two differentially methylated positions (DMPs) associated with PUFA intake in the KORA study. The DMP cg19937480, annotated to gene PRDX1, was positively associated with docosahexaenoic acid (DHA) in model 1 (beta: 2.00 × 10, 95%CI: 1.28 × 10-2.73 × 10, P value: 6.98 × 10), while cg05041783, annotated to gene MARK2, was positively associated with docosapentaenoic acid (DPA) in our fully adjusted model (beta: 9.80 × 10, 95%CI: 6.25 × 10-1.33 × 10, P value: 6.75 × 10). In the meta-analysis, we identified the CpG site (cg15951061), annotated to gene CDCA7L below Bonferroni correction (1.23 × 10) associated with eicosapentaenoic acid (EPA) intake in model 1 (beta: 2.00 × 10, 95% CI: 1.27 × 10-2.73 × 10, P value = 5.99 × 10) and we confirmed the association of cg19937480 with DHA in both models 1 and 2 (beta: 2.07 × 10, 95% CI: 1.31 × 10-2.83 × 10, P value = 1.00 × 10 and beta: 2.19 × 10, 95% CI: 1.41 × 10-2.97 × 10, P value = 5.91 × 10 respectively).
CONCLUSIONS
Our study identified three CpG sites associated with PUFA intake. The mechanisms of these sites remain largely unexplored, highlighting the novelty of our findings. Further research is essential to understand the links between CpG site methylation and PUFA outcomes.
Topics: Humans; Epigenome; DNA Methylation; Fatty Acids, Omega-3; Fatty Acids; Docosahexaenoic Acids; Repressor Proteins
PubMed: 38365790
DOI: 10.1186/s13148-024-01643-9 -
Food Science & Nutrition Oct 2023There is growing evidence that bioactive fatty acids (BFAs), including eicosapentaenoic acid (EPA; 20:5-3), docosahexaenoic acid (DHA; 22:6-3), and conjugated fatty... (Review)
Review
There is growing evidence that bioactive fatty acids (BFAs), including eicosapentaenoic acid (EPA; 20:5-3), docosahexaenoic acid (DHA; 22:6-3), and conjugated fatty acids offer multiple biological benefits and constitute ingredients in functional food development. Despite their potential, novel and alternative/nonconventional sources with unique bioactive properties to meet growing demand remain largely unexplored, poorly characterized, and their effects are not well understood. We systematically reviewed the literature to identify studies on alternative sources of BFAs, their functions, extraction, and application in the food and nutraceutical industry. Twenty studies delved into alternate sources such as plants, bacteria, and algae. Six studies found EPA and DHA as the dominant FA in algal sources, while ten studies reported several BFAs from plant sources. Five studies assessed the health benefits of docosapentaenoic acid (DPA), arachidonic acid (ARA), EPA, γ-linolenic acid (GLA), and linoleic acid (LA). Eleven studies compared the quality of oil recovered by green solvents, pressurized liquid, supercritical fluid, and assisted extraction methods. Three studies assessed the effects of assisted extraction methods and reported that these approaches improved oil yield and quality, but the findings may have limited applicability to other lipid sources. The quality of nonconventional lipids largely depends on extraction techniques. Four studies suggested methods like 1D and 2D NMR spectroscopy, LC-MS/MS; however, their analytical differences make accurate comparison inadequate. Five studies found that the incorporation of algal and seafood biolipids during product development increased EHA and DHA contents.
PubMed: 37823172
DOI: 10.1002/fsn3.3521 -
The Journal of Nutrition Dec 2008Kinetic methods in unanesthetized rodents have shown that turnover rates of arachidonic acid (AA) and docosahexaenoic acid (DHA) in brain membrane phospholipids are...
Kinetic methods in unanesthetized rodents have shown that turnover rates of arachidonic acid (AA) and docosahexaenoic acid (DHA) in brain membrane phospholipids are rapid and energy consuming and that phospholipase A(2) (PLA(2)) and acyl-CoA synthetase enzymes that regulate turnover are specific for one or the other PUFA. Thus, AA turnover in brain phospholipids was reduced, and AA-selective cytosolic cPLA(2) or acyl-CoA synthetase, as well as cyclooxygenase (COX)-2, were downregulated in brains of rats given drugs effective against bipolar disorder, whereas DHA turnover and expression of DHA-selective calcium-independent iPLA(2) were unchanged. Additionally, the brain AA and DHA cascades can be altered reciprocally by dietary or genetic conditions. Thus, following 15 wk of dietary (n-3) PUFA deprivation, DHA loss from rat brain was slowed because of reduced iPLA(2) and COX-1 expression, whereas AA-selective cPLA(2), sPLA(2), and COX-2 were upregulated, as were AA and docosapentaenoic acid concentrations. Measured rates of AA and DHA incorporation into brain represent their respective rates of metabolic consumption, because these PUFA are not synthesized de novo or converted significantly from their precursors in brain. In healthy human volunteers, positron emission tomography (PET) was used to show that the brain consumes AA and DHA at respective rates of 17.8 and 4.6 mg/d, whereas in patients with Alzheimer disease, AA consumption is elevated. In the future, PET could be used to relate human brain rates of AA and DHA consumption to liver PUFA metabolism and dietary PUFA intake.
Topics: Animals; Antimanic Agents; Arachidonic Acid; Brain; Docosahexaenoic Acids; Fatty Acids, Omega-3; Humans; Kinetics; Lithium; Models, Neurological; Phospholipases A2; Positron-Emission Tomography; Rats; Up-Regulation
PubMed: 19022981
DOI: 10.1093/jn/138.12.2515 -
The Journal of Neuroscience : the... Apr 2007The underlying cause of sporadic Alzheimer disease (AD) is unknown, but a number of environmental and genetic factors are likely to be involved. One environmental factor...
The underlying cause of sporadic Alzheimer disease (AD) is unknown, but a number of environmental and genetic factors are likely to be involved. One environmental factor that is increasingly being recognized as contributing to brain aging is diet, which has evolved markedly over modern history. Here we show that dietary supplementation with docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, in the 3xTg-AD mouse model of AD reduced the intraneuronal accumulation of both amyloid-beta (Abeta) and tau. In contrast, combining DHA with n-6 fatty acids, either arachidonic acid or docosapentaenoic acid (DPAn-6), diminished the efficacy of DHA over a 12 month period. Here we report the novel finding that the mechanism accounting for the reduction in soluble Abeta was attributable to a decrease in steady-state levels of presenilin 1, and not to altered processing of the amyloid precursor protein by either the alpha- or beta-secretase. Furthermore, the presence of DPAn-6 in the diet reduced levels of early-stage phospho-tau epitopes, which correlated with a reduction in phosphorylated c-Jun N-terminal kinase, a putative tau kinase. Collectively, these results suggest that DHA and DPAn-6 supplementations could be a beneficial natural therapy for AD.
Topics: Administration, Oral; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain Chemistry; Cells, Cultured; Cyclin-Dependent Kinase 5; Dietary Supplements; Docosahexaenoic Acids; Fatty Acids; Fatty Acids, Unsaturated; Glycogen Synthase Kinase 3; Mice; Mice, Transgenic; Presenilin-1; Protein Serine-Threonine Kinases; tau Proteins
PubMed: 17442823
DOI: 10.1523/JNEUROSCI.0055-07.2007 -
Frontiers in Nutrition 2024Depression is associated with greater functional impairment and high societal costs than many other mental disorders. Research on the association between plasma...
BACKGROUND
Depression is associated with greater functional impairment and high societal costs than many other mental disorders. Research on the association between plasma polyunsaturated fatty acids (PUFAs) levels and depression have yielded inconsistent results.
OBJECTIVE
To evaluate whether plasma n-3 and n-6 PUFAs levels are associated with depression in American adults.
METHODS
A cross-sectional study included 2053 adults (aged ≥20 y) in the National Health and Nutrition Examination Survey (NHANES), 2011-2012. The level of plasma n-3 and n-6 PUFAs were obtained for analysis. Self-reported Patient Health Questionnaire-9 (PHQ-9) was used to identify the depression status. Binary logistic regression analysis was performed to evaluate the association between quartiles of plasma n-3 and n-6 PUFAs and depression after adjustments for confounders.
RESULTS
The study of 2053 respondents over 20 years of age with a weighted depression prevalence of 7.29% comprised 1,043 men (weighted proportion, 49.13%) and 1,010 women (weighted, 50.87%), with a weighted mean (SE) age of 47.58 (0.67) years. Significantly increased risks of depression over non-depression were observed in the third quartiles (OR = 1.65, 95% CI = 1.05-2.62) for arachidonic acid (AA; 20:4n-6); the third quartiles (OR = 2.20, 95% CI = 1.20-4.05) for docosatetraenoic acid (DTA; 22:4n-6); the third (OR = 2.33, 95% CI = 1.34-4.07), and highest quartiles (OR = 1.83, 95% CI = 1.03-3.26) for docosapentaenoic acid (DPAn-6; 22:5n-6); and the third (OR = 2.18, 95% CI = 1.18-4.03) and highest quartiles (OR = 2.47, 95% CI = 1.31-4.68) for docosapentaenoic acid (DPAn-3; 22:5n-3); the second (OR = 2.13, 95% CI = 1.24-3.66), third (OR = 2.40, 95% CI = 1.28-4.50), and highest quartiles (OR = 2.24, 95% CI = 1.08-4.69) for AA/docosahexaenoic acid (DHA; 22:6n-3) ratio compared with the lowest quartile after adjusting for confounding factors.
CONCLUSION
Higher plasma levels of AA, DTA, DPAn-6, DPAn-3 PUFAs, and AA/DHA ratio may be potential risk factors for depression in US adults.
PubMed: 38544754
DOI: 10.3389/fnut.2024.1342304 -
Frontiers in Neuroscience 2023Obsessive-compulsive disorder (OCD), characterized by the presence of obsessions and/or compulsions, is often difficult to diagnose and treat in routine clinical...
INTRODUCTION
Obsessive-compulsive disorder (OCD), characterized by the presence of obsessions and/or compulsions, is often difficult to diagnose and treat in routine clinical practice. The candidate circulating biomarkers and primary metabolic pathway alteration of plasma in OCD remain poorly understood.
METHODS
We recruited 32 drug-naïve patients with severe OCD and 32 compared healthy controls and applied the untargeted metabolomics approach by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) to assess their circulating metabolic profiles. Both univariate and multivariate analyses were then utilized to filtrate differential metabolites between patients and healthy controls, and weighted Correlation Network Analysis (WGCNA) was utilized to screen out hub metabolites.
RESULTS
A total of 929 metabolites were identified, including 34 differential metabolites and 51 hub metabolites, with an overlap of 13 metabolites. Notably, the following enrichment analyses underlined the importance of unsaturated fatty acids and tryptophan metabolism alterations in OCD. Metabolites of these pathways in plasma appeared to be promising biomarkers, such as Docosapentaenoic acid and 5-Hydroxytryptophan, which may be biomarkers for OCD identification and prediction of sertraline treatment outcome, respectively.
CONCLUSION
Our findings revealed alterations in the circulating metabolome and the potential utility of plasma metabolites as promising biomarkers in OCD.
PubMed: 37332872
DOI: 10.3389/fnins.2023.1148971 -
The American Journal of Clinical... Sep 2004The n-3 fatty acid docosahexaenoic acid (DHA; 22:6n-3) is important for neural and visual functional development. In animals, 22:6n-3 deficiency is accompanied by...
BACKGROUND
The n-3 fatty acid docosahexaenoic acid (DHA; 22:6n-3) is important for neural and visual functional development. In animals, 22:6n-3 deficiency is accompanied by increased docosapentaenoic acid (DPA; 22:5n-6), which suggests that the ratio of 22:6n-3 to 22:5n-6 could be a useful biochemical marker of low n-3 fatty acid status. The n-3 fatty acid status of preschool children has not been described, and data are lacking on whether low 22:6n-3 is accompanied by high 22:5n-6 in humans.
OBJECTIVE
We determined n-3 fatty acid status and investigated the relation between 22:6n-3 and 22:5n-6 in children.
DESIGN
In Canadian children aged 18-60 mo (n = 84), the n-3 and n-6 fatty acid status of erythrocyte phosphatidylethanolamine was measured, and dietary fat intake was estimated by using a food-frequency questionnaire.
RESULTS
The mean (+/- SEM) 22:6n-3 concentration in erythrocyte phosphatidylethanolamine among children was 3.06 +/- 0.13 g/100 g fatty acids (5th-95th percentiles: 1.43-5.79 g/100 g fatty acids). Concentrations of 22:5n-6 increased with increasing 22:6n-3 concentrations in erythrocyte phosphatidylethanolamine (P < 0.01). Mean intakes of linoleic acid (18:2n-6), linolenic acid (18:3n-3), and trans fatty acids were 3.6 +/- 0.2%, 0.7 +/- 0.5%, and 2.0 +/- 1.3%, respectively. Phosphatidylethanolamine 22:6n-3 and 22:5n-3 concentrations were inversely related to the intakes of 18:2n-6 and trans fatty acids, but not to those of total fat or n-3 fatty acids.
CONCLUSIONS
The concentration of 22:5n-6 is not a useful biochemical marker of low n-3 fatty acid intake or status in the membrane phosphatidylethanolamine of preschool children. High intakes of 18:2n-6 and trans fatty acids could compromise the incorporation of 22:6n-3 into membrane phospholipids.
Topics: Biomarkers; British Columbia; Child, Preschool; Cross-Sectional Studies; Docosahexaenoic Acids; Erythrocytes; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Fatty Acids, Unsaturated; Female; Humans; Infant; Male; Nutrition Policy; Nutritional Status; Predictive Value of Tests; Surveys and Questionnaires
PubMed: 15321820
DOI: 10.1093/ajcn/80.3.768