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Lipids Jul 2023Tetracosahexaenoic acid (24:6ω-3) is an intermediate in the conversion of 18:3ω-3 to 22:6ω-3 in mammals. There is limited information about whether cells can...
Tetracosahexaenoic acid (24:6ω-3) is an intermediate in the conversion of 18:3ω-3 to 22:6ω-3 in mammals. There is limited information about whether cells can assimilate and metabolize exogenous 24:6ω-3. This study compared the effect of incubation with 24:6ω-3 on the fatty acid composition of two related cell types, primary CD3 T lymphocytes and Jurkat T cell leukemia, which differ in the integrity of the polyunsaturated fatty acid (PUFA) biosynthesis pathway. 24:6ω-3 was only detected in either cell type when cells were incubated with 24:6ω-3. Incubation with 24:6ω-3 induced similar increments in the amount of 22:6ω-3 in both cell types and modified the homeoviscous adaptations fatty acid composition induced by activation of T lymphocytes. The effect of incubation with 18:3ω-3 compared to 24:6ω-3 on the increment in 22:6ω-3 was tested in Jurkat cells because primary T cells cannot convert 18:3ω-3 to 22:6ω-3. The increment in the 22:6ω-3 content of Jurkat cells incubated with 24:6ω-3 was 19.5-fold greater than that of cells incubated with 18:3ω-3. Acyl-coA oxidase siRNA knockdown decreased the amount of 22:6ω-3 and increased the amount of 24:6ω-3 in Jurkat cells. These findings show exogenous 24:6ω-3 can be incorporated into primary human T lymphocytes and Jurkat cells and induces changes in fatty acid composition consistent with its conversion to 22:6ω-3 via a mechanism involving peroxisomal β-oxidation that is regulated independently from the integrity of the upstream PUFA synthesis pathway. One further implication is that consuming 24:6ω-3 may be an effective alternative means of achieving health benefits attributed to 20:5ω-3 and 22:6ω-3.
Topics: Animals; Humans; Fatty Acids; Jurkat Cells; Docosahexaenoic Acids; Leukemia, T-Cell; Mammals
PubMed: 37177900
DOI: 10.1002/lipd.12372 -
Journal of Nutritional Science and... 2015Metabolic syndrome is a cluster of metabolic disorders that contribute to increased cardiovascular morbidity and mortality. Although the pathogenesis of metabolic... (Review)
Review
Metabolic syndrome is a cluster of metabolic disorders that contribute to increased cardiovascular morbidity and mortality. Although the pathogenesis of metabolic syndrome is complicated, dietary lipids have been recognized as contributory factors in the development and the prevention of cardiovascular risk clustering. We investigated the physiological functions and molecular actions of functional lipids, especially omega3-polyunsaturated fatty acid (PUFA)-containing lipids, in the development of metabolic syndrome using obese model animals. Feeding of omega3-PUFA-containing lipids, such as eicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid, tetracosahexaenoic acid, and omega3-phosphatidylcholine, alleviated hepatic lipid accumulation through the suppression of lipogenic gene expression in the liver. Additionally, dietary omega3-PUFA-containing lipids increased serum adiponectin levels in obese animal models. Their molecular actions in the prevention and alleviation of metabolic syndrome could be attributed to the regulation of the activity or abundance of several transcriptional factors in the liver and adipose tissue. Dietary functional lipids would be useful to prevent or alleviate metabolic syndrome in obese animals. In particular, the function of omega3-containing lipids as dietary adiponectin inducers deserves attention with respect to alleviation of metabolic syndrome by dietary manipulation.
Topics: Adiponectin; Adipose Tissue; Animals; Diet; Fatty Acids, Omega-3; Functional Food; Humans; Liver; Metabolic Syndrome; Obesity; Transcription Factors
PubMed: 26598838
DOI: 10.3177/jnsv.61.S159 -
Journal of Oleo Science Dec 2018Tetracosahexaenoic acid (THA; 24:6n-3) is a natural, n-3 highly unsaturated fatty acid (n-3HUFA) that exists in fish, including Baltic herring (Clupea harengus) and the...
Tetracosahexaenoic acid (THA; 24:6n-3) is a natural, n-3 highly unsaturated fatty acid (n-3HUFA) that exists in fish, including Baltic herring (Clupea harengus) and the flathead flounder (Hippoglossoides dubius). In this study, natural n-3HUFAs, i.d. eicosapentaenoic acid (EPA, 20:5n-3), docosahexaenoic acid (DHA, 22:6n-3), and THA were administrated to C57BL/KsJ-db/db mice for 4 weeks and the liver and serum lipid profiles, hepatic enzyme activity, expression of mRNA related to lipid metabolism, and adiponectin serum levels were then analyzed. The results showed that THA had the highest activity in suppressing hepatic triglyceride (TG) accumulation and increase in liver weight among the test groups. Furthermore, THA increased adiponectin levels in serum. These results indicate that THA is an excellent natural n-3HUFA that can suppress the development of metabolic syndromes and circulatory system diseases. The order of the n-3HUFA activity was THA > DHA > EPA in almost all the factors examined here. In a previous study of ours, the order was DHA > DPA > EPA, so the final order was summarized as THA > DHA > DPA > EPA. This order clearly translates to the rule that "the number of double bonds and carbon atoms in the n-3HUFA structure relates to their clinical functions".
Topics: Adiponectin; Adipose Tissue; Adiposity; Animals; Body Weight; Docosahexaenoic Acids; Liver; Male; Mice, Inbred C57BL; Triglycerides
PubMed: 30429439
DOI: 10.5650/jos.ess18167 -
Journal of Lipid Research Feb 2019Tetracosahexaeoic acid (THA; 24:6n-3) is thought to be the immediate precursor of DHA in rodents; however, the relationship between THA and DHA metabolism has not been...
Tetracosahexaeoic acid (THA; 24:6n-3) is thought to be the immediate precursor of DHA in rodents; however, the relationship between THA and DHA metabolism has not been assessed in vivo. Here, we infused unesterified H-THA and C-DHA, at a steady state, into two groups of male Long-Evans rats and determined the synthesis-secretion kinetics, including daily synthesis-secretion rates of all 20-24 carbon n-3 PUFAs. We determined that the synthesis-secretion coefficient (a measure of the capacity to synthesize a given fatty acid) for the synthesis of DHA from plasma unesterified THA to be 134-fold higher than for THA from DHA. However, when considering the significantly higher endogenous plasma unesterified DHA pool, the daily synthesis-secretion rates were only 7-fold higher for DHA synthesis from THA (96.3 ± 31.3 nmol/d) compared with that for THA synthesis from DHA (11.4 ± 4.1 nmol/d). Furthermore, plasma unesterified THA was converted to DHA and secreted into the plasma at a 2.5-fold faster rate than remaining as THA itself (26.2 ± 6.3 nmol/d), supporting THA's primary role as a precursor to DHA. In conclusion, using a 3 h infusion model in rats, we demonstrate for the first time in vivo that DHA is both a product and a precursor to THA.
Topics: Animals; Docosahexaenoic Acids; Half-Life; Hydrolysis; Isotope Labeling; Kinetics; Male; Rats
PubMed: 30573561
DOI: 10.1194/jlr.M090373 -
Biomolecules Oct 2022Disordered gut microbiota (GM) as the co-contributor of atrial fibrillation (AF) and hypertension (HTN) might be associated with AF risk in HTN. This study aimed to...
Disordered gut microbiota (GM) as the co-contributor of atrial fibrillation (AF) and hypertension (HTN) might be associated with AF risk in HTN. This study aimed to explore the altered GM community and metabolic patterns between 27 HTN patients with AF (HTN-AF) and 27 non-AF HTN patients through fecal metagenomic and serum metabolomic analysis. Compared to non-AF HTN patients, significant microbial alterations (p = 0.004), including increased microbial diversity (p < 0.05), shifted enterotype dominated by Prevotella to Bacteroides, and abundant disease-linked genera Ruminococcus, Streptococcus, Veillonella, Dorea, and Enterococcus, were observed in HTN-AF patients. A species-based random forest prediction model was associated with the risk of AF occurrence in HTN patients. Furthermore, GM metabolic profiles dramatically differed between HTN and HTN-AF patients, especially the imbalance of saturated and unsaturated fatty acids. In HTN-AF patients, circulating palmitic acid and arachidonic acid levels were significantly elevated, while the levels of tetracosahexaenoic acid, oleic acid, linoleic acid, and stearic acid were decreased (p < 0.001, VIP > 1), mediating 85.99% of gut microbial indirect effects on AF (p < 0.001). Thus, our findings preliminarily indicated that exacerbated dysbiosis of GM and relevant metabolites was associated with high AF susceptibility and might be a potential target for AF prediction and prevention in HTN.
Topics: Humans; Atrial Fibrillation; Gastrointestinal Microbiome; Hypertension; Stearic Acids; Arachidonic Acids; Linoleic Acids; Palmitic Acids; Oleic Acids
PubMed: 36291654
DOI: 10.3390/biom12101445 -
FEBS Letters Sep 2016Docosahexaenoic acid (22:6n-3) supplementation in humans causes eicosapentaenoic acid (20:5n-3) levels to rise in plasma, but not in neural tissue where 22:6n-3 is the...
Metabolic fate of docosahexaenoic acid (DHA; 22:6n-3) in human cells: direct retroconversion of DHA to eicosapentaenoic acid (20:5n-3) dominates over elongation to tetracosahexaenoic acid (24:6n-3).
Docosahexaenoic acid (22:6n-3) supplementation in humans causes eicosapentaenoic acid (20:5n-3) levels to rise in plasma, but not in neural tissue where 22:6n-3 is the major omega-3 in phospholipids. We determined whether neuronal cells (Y79 and SK-N-SH) metabolize 22:6n-3 differently from non-neuronal cells (MCF7 and HepG2). We observed that (13) C-labeled 22:6n-3 was primarily esterified into cell lipids. We also observed that retroconversion of 22:6n-3 to 20:5n-3 was 5- to 6-fold greater in non-neural compared to neural cells and that retroconversion predominated over elongation to tetracosahexaenoic acid (24:6n-3) by 2-5-fold. The putative metabolic intermediates, (13) C-labeled 22:5n-3 and (13) C-labeled 24:5n-3, were not detected in our assays. Analysis of the expression of enzymes involved in fatty acid beta-oxidation revealed that MCF7 cells abundantly expressed the mitochondrial enzymes CPT1A, ECI1, and DECR1, whereas the peroxisomal enzyme ACOX1 was abundant in HepG2 cells, thus suggesting that the initial site of 22:6n-3 oxidation depends on the cell type. Our data reveal that non-neural cells more actively metabolize 22:6n-3 to 20:5n-3 via channeled retroconversion, while neural cells retain 22:6n-3.
Topics: Carnitine O-Palmitoyltransferase; Docosahexaenoic Acids; Dodecenoyl-CoA Isomerase; Eicosapentaenoic Acid; Hep G2 Cells; Humans; MCF-7 Cells
PubMed: 27543786
DOI: 10.1002/1873-3468.12368 -
British Journal of Pharmacology Dec 2011Peroxisomes are indispensable organelles in higher eukaryotes. They are essential for a number of important metabolic pathways, including fatty acid α- and... (Review)
Review
Peroxisomes are indispensable organelles in higher eukaryotes. They are essential for a number of important metabolic pathways, including fatty acid α- and β-oxidation, and biosynthesis of etherphospholipids and bile acids. However, the peroxisomal membrane forms an impermeable barrier to these metabolites. Therefore, peroxisomes need specific transporter proteins to transfer these metabolites across their membranes. The mammalian peroxisomal membrane harbours three ATP-binding cassette (ABC) transporters. In recent years, significant progress has been made in unravelling the functions of these ABC transporters. There is ample evidence that they are involved in the transport of very long-chain fatty acids, pristanic acid, di- and trihydroxycholestanoic acid, dicarboxylic acids and tetracosahexaenoic acid (C24:6ω3). Surprisingly, only one disease is associated with a deficiency of a peroxisomal ABC transporter. Mutations in the ABCD1 gene encoding the peroxisomal ABC transporter adrenoleukodystrophy protein are the cause for X-linked adrenoleukodystrophy, an inherited metabolic storage disorder. This review describes the current state of knowledge on the mammalian peroxisomal ABC transporters with a particular focus on their function in metabolite transport.
Topics: ATP-Binding Cassette Transporters; Animals; Disease Models, Animal; Humans; Metabolic Diseases; Mutation; Peroxisomes; Polymorphism, Single Nucleotide; Protein Transport; Tissue Distribution
PubMed: 21488864
DOI: 10.1111/j.1476-5381.2011.01435.x -
Lipids May 2018The rate at which dietary α-linolenic acid (ALA) is desaturated and elongated to its longer-chain n-3 polyunsaturated fatty acid (PUFA) in humans is not agreed upon. In...
Quantitation of Human Whole-Body Synthesis-Secretion Rates of Docosahexaenoic Acid and Eicosapentaenoate Acid from Circulating Unesterified α-Linolenic Acid at Steady State.
The rate at which dietary α-linolenic acid (ALA) is desaturated and elongated to its longer-chain n-3 polyunsaturated fatty acid (PUFA) in humans is not agreed upon. In this study, we applied a methodology developed using rodents to investigate the whole-body, presumably hepatic, synthesis-secretion rates of esterified n-3 PUFA from circulating unesterified ALA in 2 healthy overweight women after 10 weeks of low-linoleate diet exposure. During continuous iv infusion of d5-ALA, 17 arterial blood samples were collected from each subject at -10, 0, 10, 20, 40, 60, 80, 100, 120, 150, 180, and 210 min, and at 4, 5, 6, 7, and 8 h after beginning infusion. Plasma esterified d5-n-3 PUFA concentrations were plotted against the infusion time and fit to a sigmoidal curve using nonlinear regression. These curves were used to estimate kinetic parameters using a kinetic analysis developed using rodents. Calculated synthesis-secretion rates of esterified eicosapentaenoate, n-3 docosapentaenoate, docosahexaenoic acid, tetracosapentaenate, and tetracosahexaenoate from circulating unesterified ALA were 2.1 and 2.7; 1.7 and 5.3; 0.47 and 0.27; 0.30 and 0.30; and 0.32 and 0.27 mg/day for subjects S01 and S02, respectively. This study provides new estimates of whole-body synthesis-secretion rates of esterified longer-chain n-3 PUFA from circulating unesterified ALA in human subjects. This method now can be extended to study factors that regulate human whole-body PUFA synthesis-secretion in health and disease.
Topics: Adolescent; Adult; Body Mass Index; Docosahexaenoic Acids; Eicosapentaenoic Acid; Female; Healthy Volunteers; Humans; Middle Aged; Young Adult; alpha-Linolenic Acid
PubMed: 30074625
DOI: 10.1002/lipd.12055 -
Scientific Reports Feb 2017Cervical cancer (CC) still remains a common and deadly malignancy among females in developing countries. More accurate and reliable diagnostic methods/biomarkers should...
Cervical cancer (CC) still remains a common and deadly malignancy among females in developing countries. More accurate and reliable diagnostic methods/biomarkers should be discovered. In this study, we performed a comprehensive analysis of metabolomics (285 samples) and transcriptomics (52 samples) on the potential diagnostic implication and metabolic characteristic description in cervical cancer. Sixty-two metabolites were different between CC and normal controls (NOR), in which 5 metabolites (bilirubin, LysoPC(17:0), n-oleoyl threonine, 12-hydroxydodecanoic acid and tetracosahexaenoic acid) were selected as candidate biomarkers for CC. The AUC value, sensitivity (SE), and specificity (SP) of these 5 biomarkers were 0.99, 0.98 and 0.99, respectively. We further analysed the genes in 7 significantly enriched pathways, of which 117 genes, that were expressed differentially, were mainly involved in catalytic activity. Finally, a fully connected network of metabolites and genes in these pathways was built, which can increase the credibility of our selected metabolites. In conclusion, our biomarkers from metabolomics could set a path for CC diagnosis and screening. Our results also showed that variables of both transcriptomics and metabolomics were associated with CC.
Topics: Adult; Aged; Biomarkers, Tumor; Female; Gene Expression Profiling; Humans; Metabolome; Middle Aged; ROC Curve; Sensitivity and Specificity; Uterine Cervical Neoplasms
PubMed: 28225065
DOI: 10.1038/srep43353 -
Journal of Lipid Research Dec 2019
PubMed: 31792023
DOI: 10.1194/jlr.ERR119000440