Omega-3 fatty acids increase the arachidonic acid content of liver cholesterol ester and plasma triacylglycerol fractions in the rat.
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ABSTRACT:
SUBMITTER: Garg ML
PROVIDER: S-EPMC1138773 | biostudies-other | 1989 Jul
REPOSITORIES: biostudies-other
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Project description:Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) protect against cardiovascular disease by largely unknown mechanisms. We tested the hypothesis that EPA and DHA may compete with arachidonic acid (AA) for the conversion by cytochrome P450 (CYP) enzymes, resulting in the formation of alternative, physiologically active, metabolites. Renal and hepatic microsomes, as well as various CYP isoforms, displayed equal or elevated activities when metabolizing EPA or DHA instead of AA. CYP2C/2J isoforms converting AA to epoxyeicosatrienoic acids (EETs) preferentially epoxidized the ?-3 double bond and thereby produced 17,18-epoxyeicosatetraenoic (17,18-EEQ) and 19,20-epoxydocosapentaenoic acid (19,20-EDP) from EPA and DHA. We found that these ?-3 epoxides are highly active as antiarrhythmic agents, suppressing the Ca(2+)-induced increased rate of spontaneous beating of neonatal rat cardiomyocytes, at low nanomolar concentrations. CYP4A/4F isoforms ?-hydroxylating AA were less regioselective toward EPA and DHA, catalyzing predominantly ?- and ? minus 1 hydroxylation. Rats given dietary EPA/DHA supplementation exhibited substantial replacement of AA by EPA and DHA in membrane phospholipids in plasma, heart, kidney, liver, lung, and pancreas, with less pronounced changes in the brain. The changes in fatty acids were accompanied by concomitant changes in endogenous CYP metabolite profiles (e.g. altering the EET/EEQ/EDP ratio from 87:0:13 to 27:18:55 in the heart). These results demonstrate that CYP enzymes efficiently convert EPA and DHA to novel epoxy and hydroxy metabolites that could mediate some of the beneficial cardiovascular effects of dietary ?-3 fatty acids.
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Project description:The regiospecific characteristics of n-3 polyunsaturated fatty acids (PUFAs) in triacylglycerol (TAG) significantly affect the physicochemical and physiological properties of marine fish oils. In this study, the TAG molecular species composition and positional distributions of fatty acids were investigated in three marine fish species rich in omega-3 PUFAs (anchovy, tuna, and salmon). The regiospecific distribution of the fatty acids was measured with the allylmagnesium bromide (AMB) degradation method. The TAG compositions were analyzed with HPLC and the TAG molecular species were identified with APCI/MS. DHA was preferentially distributed at the sn-2 position of TAG, whereas EPA was evenly distributed along the glycerol backbone. The combinations of FAs, DDO, EOP, EPS, DSS, OOS, and PPS were the predominant TAG molecular species, and OOP, DOS, and DPoPo were the characteristic TAG molecules in the anchovy, salmon, and tuna, respectively. These data can be used to distinguish other marine fish species. The TAG composition categorized by TCN and ECN showed well-structured distributions, with double or triple peaks. These findings should greatly extend the use of marine fish oils in food production and may significantly affect the future development of the fish oil industry.
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Project description:Essential fatty acids (FA) are not only energy-rich molecules; they are also an important component of the membrane bilayer and recently have been implicated in induction of fatty acid synthase (FAS) and other genes. Using gene chip analysis, we have found that arachidonic acid (AA), an omega-6 fatty acid, induced 11 genes that are regulated by NFkappaB. We verified gene induction by omega-6 fatty acids including COX2, IKBA, NFKB, GMCSF, IL1B, CXCL1, TNFA, IL6, LTA, IL8, PPARG, and ICAM1 using qRTPCR. PGE2 synthesis was increased within 5min of addition of AA. Analysis of upstream signal transduction showed that within 5min of FA addition, phophatidylinositol 3-kinase (PI3K) was significantly activated followed by activation of Akt at 30min. ERK1 and 2, p38, and SAPK/JNK were not phosphorylated after omega-6 FA addition. Thirty minutes after FA addition, we found a significant 3-fold increase in translocation of NFkappaB transcription factor to the nucleus. Addition of non-steroidal anti-inflammatory drug (NSAID) caused a decrease in cox-2 protein synthesis, PGE2 synthesis as well as inhibition of PI3K activation. We have previously shown that AA induced proliferation is also blocked (P<0.001) by PI3K inhibitor LY294002. LY294002 also significantly inhibited the AA induced gene expression of COX2, IL1B, GMCSF, and ICAM1. Taken together, the data suggests that AA via conversion to PGE2 plays an important role in stimulation of growth related genes and proliferation via PI3K signaling and NFkappaB translocation to the nucleus. Keywords: Time course of Prostate Cancer Activation by Arachidonic Acid
2006-01-01 | GSE3737 | GEO
Project description: Not available
| S-EPMC8243522 | biostudies-literature
Project description:We have previously demonstrated that carrying the apolipoprotein (apo) E epsilon 4 (E4+) genotype disrupts omega-3 fatty acids (n?-?3 PUFA) metabolism. Here we hypothesise that the postprandial clearance of n?-?3 PUFA from the circulation is faster in E4+ compared to non-carriers (E4-). The objective of the study was to investigate the fasted and postprandial fatty acid (FA) profile of triacylglycerol-rich lipoprotein (TRL) fractions: Sf >400 (predominately chylomicron CM), Sf 60?-?400 (VLDL1), and Sf 20?-?60 (VLDL2) according to APOE genotype.Postprandial TRL fractions were obtained in 11 E4+ (?3/?4) and 12 E4- (?3/?3) male from the SATgen? study following high saturated fat diet?+?3.45 g/d of docosahexaenoic acid (DHA) for 8-wk. Blood samples were taken at fasting and 5-h after consuming a test-meal representative of the dietary intervention. FA were characterized by gas chromatography.At fasting, there was a 2-fold higher ratio of eicosapentaenoic acid (EPA) to arachidonic acid (P?=?0.046) as well as a trend towards higher relative% of EPA (P?=?0.063) in the Sf >400 fraction of E4+. Total n?-?3 PUFA in the Sf 60?-?400 and Sf 20?-?60 fractions were not APOE genotype dependant. At 5 h, there was a trend towards a time?×?genotype interaction (P?=?0.081) for EPA in the Sf >400 fraction. When sub-groups were form based on the level of EPA at baseline within the Sf >400 fraction, postprandial EPA (%) was significantly reduced only in the high-EPA group. EPA at baseline significantly predicted the postprandial response in EPA only in E4+ subjects (R2?=?0.816).Despite the DHA supplement contain very low levels of EPA, E4+ subjects with high EPA at fasting potentially have disrupted postprandial n?-?3 PUFA metabolism after receiving a high-dose of DHA.Registered at clinicaltrials.gov/show/NCT01544855.
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Project description:BACKGROUND:Preterm birth is the leading cause of death in children under five. A recent Cochrane review found a 42% reduction in early preterm birth (< 34 weeks' gestation) and 11% reduction in preterm birth (< 37 weeks' gestation) with omega-3 fatty acid supplementation. To assist in the development of implementation strategies to increase pregnant women's omega-3 fatty acid intake, we assessed the awareness of Australian pregnant women about preterm birth, their nutrition and supplementation behaviours during pregnancy, and intentions to increase omega-3 fatty acid intake. METHODS:A ten-minute survey was conducted online to assess the knowledge, attitudes, behaviours, and intentions of Australian pregnant women across three domains: (1) preterm birth; (2) nutrition and supplementation during pregnancy; and (3) omega-3 fatty acid consumption to prevent preterm birth. Participants were recruited from Survey Sampling International's research panels. RESULTS:Of the 763 women who completed the survey, less than two-thirds had heard of preterm birth. Over 55% of respondents had changed their diet during pregnancy and a prenatal dietary supplement was consumed by 82% of the women surveyed. Respondents' main source of information about preterm birth and nutrition during pregnancy was from a health professional. When asked about their intentions to increase their omega-3 fatty acid intake following a health professional's recommendation, the vast majority of participants indicated they would increase their omega-3 fatty acid intake (90%). When a hypothetical scenario was presented of an omega-3 fatty acid supplement being offered from a health service at no cost, the number of respondents who selected they would increase their intake through supplementation increased from 54 to 79%. CONCLUSIONS:The main information source for women about preterm birth and dietary supplementation recommendations during pregnancy is their health professional. Therefore, informing women about ways to prevent preterm birth, including the role of omega-3 fatty acids, should occur during antenatal visits. The results from our study are useful for clinicians caring for pregnant women and for the next stage of translation of the Cochrane review findings - the design of implementation strategies to increase the intake of omega-3 fatty acids during pregnancy where needed.
| S-EPMC6857157 | biostudies-literature
Project description:Long-chain n-3 polyunsaturated fatty acids (Omega-3) and anti-diabetic drugs thiazolidinediones (TZDs) exhibit additive effects in counteraction of dietary obesity and associated metabolic dysfunctions in mice. The underlying mechanisms need to be clarified. Here, we aimed to learn whether the futile cycle based on the hydrolysis of triacylglycerol and re-esterification of fatty acids (TAG/FA cycling) in white adipose tissue (WAT) could be involved. We compared Omega-3 (30 mg/g diet) and two different TZDs-pioglitazone (50 mg/g diet) and a second-generation TZD, MSDC-0602K (330 mg/g diet)-regarding their effects in C57BL/6N mice fed an obesogenic high-fat (HF) diet for 8 weeks. The diet was supplemented or not by the tested compound alone or with the two TZDs combined individually with Omega-3. Activity of TAG/FA cycle in WAT was suppressed by the obesogenic HF diet. Additive effects in partial rescue of TAG/FA cycling in WAT were observed with both combined interventions, with a stronger effect of Omega-3 and MSDC-0602K. Our results (i) supported the role of TAG/FA cycling in WAT in the beneficial additive effects of Omega-3 and TZDs on metabolism of diet-induced obese mice, and (ii) showed differential modulation of WAT gene expression and metabolism by the two TZDs, depending also on Omega-3.
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Project description:More than a dozen epidemiological studies have reported that reduced levels or intake of omega-3 fatty acids or fish consumption is associated with increased risk for age-related cognitive decline or dementia such as Alzheimer's disease (AD). Increased dietary consumption or blood levels of docosahexaenoic acid (DHA) appear protective for AD and other dementia in multiple epidemiological studies; however, three studies suggest that the ApoE4 genotype limits protection. DHA is broadly neuroprotective via multiple mechanisms that include neuroprotective DHA metabolites, reduced arachidonic acid metabolites, and increased trophic factors or downstream trophic signal transduction. DHA is also protective against several risk factors for dementia including head trauma, diabetes, and cardiovascular disease. DHA is specifically protective against AD via additional mechanisms: It limits the production and accumulation of the amyloid beta peptide toxin that is widely believed to drive the disease; and it also suppresses several signal transduction pathways induced by Abeta, including two major kinases that phosphorylate the microtubule-associated protein tau and promote neurofibrillary tangle pathology. Based on the epidemiological and basic research data, expert panels have recommended the need for clinical trials with omega-3 fatty acids, notably DHA, for the prevention or treatment of age-related cognitive decline--with a focus on the most prevalent cause, AD. Clinical trials are underway to prevent and treat AD. Results to-date suggest that DHA may be more effective if it is begun early or used in conjunction with antioxidants.
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Project description:In the present study, the beneficial effects of proteasome inhibitor treatment in reducing ethanol-induced steatosis were investigated. A microarray analysis was performed on the liver of rats injected with PS-341 (Bortezomib, Velcade), and the results showed that proteasome inhibitor treatment significantly reduced the mRNA expression of SREBP-1c, and the downstream lipogenic enzymes, such as fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC), which catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting step in fatty acid synthesis. ELOVL6, which is responsible for fatty acids long chain elongation, was also significantly downregulated by proteasome inhibitor treatment. Moreover, PS-341 administration significantly reduced the expression of acyl-glycerol-3-phosphate acyltransferase (AGPAT), and diacylglycerol acyltransferase (DGAT), enzyme involved in triacylglycerol (TAG) synthesis. Finally, PS-341 was found to downregulate the enzyme 3-hydroxy-3-methylglutaryl-CoenzymeA synthase (HMG-CoA synthase) that is responsible for cholesterol synthesis. Proteasome inhibitor was also found to play a role in intestinal lipid adsorption because apolipoproteins A (apoA-I, apoAII, apoA-IV and ApoCIII) were downregulated by proteasome inhibitor treatment, especially ApoA-II that is known to be a marker of alcohol consumption. Proteasome inhibitor treatment also decreased apobec-1 complementation factor (ACF) leading to lower level of editing and production of ApoB protein. Moreover apolipoprotein C-III, a major component of chylomicrons was significantly downregulated. However, lipoprotein lipase (Lpl) and High density lipoprotein binding protein (Hdlbp) mRNA levels were increased by proteasome inhibitor treatment. These results suggested that proteasome inhibitor treatment could be used to reduce the alcohol-enhanced lipogenesis and alcohol-induced liver steatosis. A morphologic analysis, performed on the liver of rats fed ethanol for one month and treated with PS-341, showed that proteasome inhibitor treatment significantly decreased ethanol-induced liver steatosis. SREBP-1c, FAS and ACC were increased by ethanol feeding alone, but were significantly decreased when proteasome inhibitor was administered to rats fed ethanol. Our results also show that both mRNA and protein levels of these lipogenic enzymes, up regulated by ethanol, were then downregulated when proteasome inhibitor was administered to rats fed ethanol. It was also confirmed that alcohol feeding caused an increase in AGPAT and DGAT, which was prevented by proteasome inhibitor treatment of the animal fed ethanol. Chronic alcohol feeding did not affect the gene expression of HMG-CoA synthase. However, PS341 administration significantly reduced the HMG-CoA synthase mRNA levels, confirming the results obtained with the microarray analysis. C/EBP transcription factors alpha (CCAAT/enhancer-binding protein alpha) has been shown to positively regulate SREBP-1c mRNA expression, thus regulating lipogenesis. Proteasome inhibition caused a decrease in C/EBP alpha mRNA expression, indicating that C/EBP downregulation may be the mechanism by which proteasome inhibitor treatment reduced lipogenesis. In conclusion, our results indicate that proteasome activity is not only involved in downregulating fatty acid synthesis and triacylglycerol synthesis, but also cholesterol synthesis and intestinal lipid adsorption. Proteasome inhibitor, administrated at a non-toxic low dose, played a beneficial role in reducing lipogenesis caused by chronic ethanol feeding and these beneficial effects are obtained because of the specificity and reversibility of the proteasome inhibitor used.
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