Polyunsaturated Fatty Acids Eicosapentaenoic Acid Research Articles

A U-shaped association between consumption of marine n-3 fatty acids and development of atrial fibrillation/atrial flutter--a Danish cohort study

Previous studies have suggested a lower risk of atrial fibrillation (AF) with higher intakes of fish and marine n-3 polyunsaturated fatty acids (PUFAs), but the results have been inconsistent. The aim was to investigate the association between consumption of marine n-3 PUFA and development of AF. A total of 57 053 Danish participants 50-64 years of age were enrolled in the Diet, Cancer, and Health Cohort Study between 1993 and 1997. Dietary intake of fish and marine n-3 PUFA was assessed by a semi-quantitative food frequency questionnaire. In total, 3345 incident cases of AF occurred over 13.6 years. Multivariate Cox regression analyses (3284 cases and 55 246 participants) using cubic splines showed a U-shaped association between consumption of marine n-3 PUFA and risk of incident AF, with the lowest risk of AF at a moderate intake of 0.63 g/day. For quintiles of marine n-3 PUFA intake, a 13% statistically significant lower risk of AF was seen in the middle vs. lowest quintile: Q1 reference, Q2 HR 0.92 (95% CI 0.82-1.03), Q3 HR 0.87 (95% CI 0.78-0.98), Q4 HR 0.96 (95% CI 0.86-1.08), and Q5 HR 1.05 (95% CI 0.93-1.18). Intake of total fish, fatty fish, and the individual n-3 PUFA eicosapentaenoic acid, docosahexaenoic acid, and docosapentaenoic acid also showed U-shaped associations with incident AF. We found a U-shaped association between consumption of marine n-3 PUFA and risk of incident AF, with the lowest risk close to the median intake of total marine n-3 PUFA (0.63 g/day).

Possibility of Polyunsaturated Fatty Acids for the Prevention and Treatment of Neuropsychiatric Illnesses

Increasing evidence from the fields of neurophysiology and neuropathology has uncovered the role of polyunsaturated fatty acids (PUFA) in protecting neuronal cells from oxidative damage, controlling inflammation, regulating neurogenesis, and preserving neuronal function. Numerous epidemiological studies have shown that deficits in the dietary PUFA docosahexaenoic acid and eicosapentaenoic acid are associated with the onset and progression of neuropsychiatric illnesses such as dementia, schizophrenia, depression, and posttraumatic stress disorder (PTSD). Recent clinical trials have offered compelling evidence that suggests that n-3 PUFA could reduce depressive, psychotic, and suicidal symptoms, as well as aggression. Although many studies have had the validity of their results questioned because of small sample size, several studies have indicated that n-3 PUFA are useful therapeutic tools for the treatment of dementia, major depression, bipolar disorder, and PTSD. These findings suggest that the pharmacological and nutritional actions of n-3 PUFA may be beneficial in certain neuropsychiatric illnesses. This review article outlines the role of PUFA in neurodevelopment and the regulatory mechanisms in neuronal stem cell differentiation and also the possible use of PUFA as a prescription medicine for the prophylaxis or treatment of neuropsychiatric illnesses such as dementia, mood disorder, and PTSD.

Polyunsaturated fatty acid biosynthesis in myxobacteria: different PUFA synthases and their product diversity

Polyunsaturated fatty acids (PUFAs), particularly the omega-3 long-chain PUFAs (LC-PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are well known for their beneficial health effects. The obvious limitation of the present EPA/DHA key source, fish oil, demands for alternative and sustainable PUFA resources and several biotechnological approaches addressing this problem are currently under development. Different marine microorganisms are known to produce PUFAs de novo under strictly anaerobic conditions employing polyketide synthase (PKS)-like enzymes known as PUFA synthases. Here, we report for the first time the characterization of such PUFA synthases from terrestrial origin. Two distinct types of PUFA biosynthetic gene clusters were discovered, originating from linoleic acid producing myxobacteria of the genus Sorangium as well as from species of the recently discovered myxobacterial genus Aetherobacter, that turned out to be prolific producers of EPA and DHA. The identified biosynthetic pathways differ significantly from the marine systems in terms of gene organization, catalytic domain arrangement, and sequence identity of the encoded PUFA synthases. Notably, a unique domain, which most likely acts as 1-acylglycerol-3-phosphate O-acyltransferase, was identified in these myxobacterial PUFA synthases. As the native producer strains grow slowly, are difficult to handle, and genetic modification has proven difficult, synthetic biotechnology approaches were applied to establish a heterologous production platform in the myxobacterial model strain Myxococcus xanthus.

Serum Omega-3 Polyunsaturated Fatty Acids and Risk of Incident Type 2 Diabetes in Men: The Kuopio Ischemic Heart Disease Risk Factor Study

OBJECTIVE The relationship between fish or omega-3 polyunsaturated fatty acids (PUFAs) and type 2 diabetes is inconclusive. Even contaminants in fish, such as mercury, may modify the effects. We investigated the associations between serum omega-3 PUFAs eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), α-linolenic acid (ALA), hair mercury, and risk of incident type 2 diabetes in middle-aged and older Finnish men. RESEARCH DESIGN AND METHODS A total of 2,212 men from the prospective, population-based Kuopio Ischemic Heart Disease Risk Factor study, aged 42-60 years and free of type 2 diabetes at baseline in 1984-1989, were investigated. Serum PUFA and hair mercury were used as biomarkers for exposure. Dietary intakes were assessed with 4-day food recording. Type 2 diabetes was assessed by self-administered questionnaires and fasting and 2-h oral glucose tolerance test blood glucose measurement at re-examination rounds 4, 11, and 20 years after the baseline and by record linkage to hospital discharge registry and reimbursement register on diabetes medication expenses. Cox proportional hazards models were used to analyze associations. RESULTS During the average follow-up of 19.3 years, 422 men developed type 2 diabetes. Men in the highest versus the lowest serum EPA + DPA + DHA quartile had 33% lower multivariate-adjusted risk for type 2 diabetes (95% CI 13-49; P trend 0.01). No statistically significant associations were observed with serum or dietary ALA, dietary fish or EPA + DHA, or hair mercury. CONCLUSIONS Serum long-chain omega-3 PUFA concentration, an objective biomarker for fish intake, was associated with long-term lower risk of type 2 diabetes.

Polyunsaturated fatty acid associations with dopaminergic indices in major depressive disorder

Dopaminergic function is thought to be altered in major depression and, in animal studies, is reduced in omega-3 polyunsaturated fatty acid (PUFA) deficiency states. Therefore we studied PUFAs and resting prolactin, a marker for dopaminergic tone, and cerebrospinal fluid homovanillic acid (HVA), the chief dopamine metabolite. In medication-free adults (n = 23) with DSM-IV major depressive disorder (MDD), we measured plasma phospholipid levels of omega-3 PUFAs docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), the omega-6 PUFA arachidonic acid (AA), and plasma prolactin levels before and after administration of dl-fenfluramine (FEN). In a subset of patients (n = 14), cerebrospinal fluid levels of HVA and the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were obtained through lumbar puncture. Baseline prolactin was negatively correlated with omega-3 PUFAs (logDHA, F(1,21) = 20.380, p < 0.001; logEPA, F(1,21) = 10.051, p = 0.005) and positively correlated with logAA:DHA (F(1,21) = 15.263, p = 0.001), a measure of omega-6/omega-3 balance. LogDHA was negatively correlated with CSF HVA (Spearman's ρ = -0.675, p = 0.008) but not 5-HIAA (Spearman's ρ = -0.143, p = 0.626) after controlling for sex and HVA - 5-HIAA correlation. PUFAs did not predict the magnitude of the FEN-stimulated change in prolactin, considered to be a serotonin effect. The robust relationship of omega-3 PUFAs with dopaminergic but not serotonergic indices suggests that omega-6:omega-3 balance may impact depression pathophysiology through effects on the dopaminergic system.

Fortification of Foods with Omega-3 Polyunsaturated Fatty Acids

A $600 million nutritional supplements market growing at 30% every year attests to consumer awareness of, and interests in, health benefits attributed to these supplements. For over 80 years the importance of polyunsaturated fatty acid (PUFA) consumption for human health has been established. The FDA recently approved the use of ω-3 PUFAs in supplements. Additionally, the market for ω-3 PUFA ingredients grew by 24.3% last year, which affirms their popularity and public awareness of their benefits. PUFAs are essential for normal human growth; however, only minor quantities of the beneficial ω-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are synthesized by human metabolism. Rather PUFAs are obtained via dietary or nutritional supplementation and modified into other beneficial metabolites. A vast literature base is available on the health benefits and biological roles of ω-3 PUFAs and their metabolism; however, information on their dietary sources and palatability of foods incorporated with ω-3 PUFAs is limited. DHA and EPA are added to many foods that are commercially available, such as infant and pet formulae, and they are also supplemented in animal feed to incorporate them in consumer dairy, meat, and poultry products. The chief sources of EPA and DHA are fish oils or purified preparations from microalgae, which when added to foods, impart a fishy flavor that is considered unacceptable. This fishy flavor is completely eliminated by extensively purifying preparations of n-3 PUFA sources. While n-3 PUFA lipid autoxidation is considered the main cause of fishy flavor, the individual oxidation products identified thus far, such as unsaturated carbonyls, do not appear to contribute to fishy flavor or odor. Alternatively, various compound classes such as free fatty acids and volatile sulfur compounds are known to impart fishy flavor to foods. Identification of the causative compounds to reduce and eventually eliminate fishy flavor is important for consumer acceptance of PUFA-fortified foods. [Supplementary materials are available for this article. Go to the publisher's online edition of Critical Reviews in Food Science and Nutrition for the following free supplemental files: Additional text, tables, and figures.]

Association between serum omega-3 to omega-6 polyunsaturated fatty acid ratio and cardiovascular events in a general Japanese population

Inflammation is recognized to play an important role in the development of atherosclerotic diseases, such as coronary heart disease (CHD). Polyunsaturated fatty acids (PUFAs) are important constituents of cell membrane phospholipids, and the phospholipids of inflammatory cells are rich in omega-6 PUFA arachidonic acid (AA), with low amounts of omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) [1]. However, AA acts as a source of pro-inflammatory eicosanoids, whereas both EPA and DHA reduce AA-derived eicosanoids and pro-inflammatory cytokines and produce anti-inflammatory resolvins and protectins [1–3].

Unusually High Levels of n‐6 Polyunsaturated Fatty Acids in Whale Sharks and Reef Manta Rays

Fatty acid (FA) signature analysis has been increasingly used to assess dietary preferences and trophodynamics in marine animals. We investigated FA signatures of connective tissue of the whale shark Rhincodon typus and muscle tissue of the reef manta ray Manta alfredi. We found high levels of n-6 polyunsaturated fatty acids (PUFA), dominated by arachidonic acid (20:4n-6; 12–17 % of total FA), and comparatively lower levels of the essential n-3 PUFA—eicosapentaenoic acid (20:5n-3; ~1 %) and docosahexaenoic acid (22:6n-3; 3–10 %). Whale sharks and reef manta rays are regularly observed feeding on surface aggregations of coastal crustacean zooplankton during the day, which generally have FA profiles dominated by n-3 PUFA. The high levels of n-6 PUFA in both giant elasmobranchs raise new questions about the origin of their main food source.

Omega-3 Polyunsaturated Fatty Acid (PUFA) Status in Major Depressive Disorder With Comorbid Anxiety Disorders

Although lower levels of omega-3 polyunsaturated fatty acids (PUFAs) are found in major depressive disorder, less is known about PUFA status and anxiety disorders. Medication-free participants with DSM-IV-defined major depressive disorder (MDD), with (n = 18) and without (n = 41) comorbid DSM-IV anxiety disorders, and healthy volunteers (n = 62) were recruited from October 2006 to May 2010 for mood disorder studies at the New York State Psychiatric Institute. Participants were 18-73 years of age (mean age, 35.8 ± 12.6 years). Depression and anxiety severity was assessed using depression and anxiety subscales from the 17-item Hamilton Depression Rating Scale. Plasma PUFAs eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) and the ratio of arachidonic acid (AA; 22:4n-6) to EPA (AA:EPA) were quantified. This secondary analysis employed analysis of variance with a priori planned contrasts to test for diagnostic group differences in log-transformed PUFA levels (logDHA, logEPA, and logAA:EPA). Plasma levels of logDHA (F(2,118) = 4.923, P = .009), logEPA (F(2,118) = 6.442, P = .002), and logAA:EPA (F(2,118) = 3.806, P = .025) differed across groups. Participants with MDD had lower logDHA (t(118) = 2.324, P = .022) and logEPA (t(118) = 3.175, P = .002) levels and higher logAA:EPA levels (t(118) = -2.099, P = .038) compared with healthy volunteers. Lower logDHA (t(118) = 2.692, P = .008) and logEPA (t(118) = 2.524, P = .013) levels and higher logAA:EPA levels (t(118) = -2.322, P = .022) distinguished anxious from nonanxious MDD. Depression severity was not associated with PUFA plasma levels; however, anxiety severity across the entire sample correlated negatively with logDHA (r(p) = -0.22, P = .015) and logEPA (r(p) = -0.25, P = .005) levels and positively with logAA:EPA levels (r(p) = 0.18, P = .043). The presence and severity of comorbid anxiety were associated with the lowest EPA and DHA levels. Further studies are needed to elucidate whether omega-3 PUFA supplementation may preferentially alleviate MDD with more severe anxiety.

Polyunsaturated fatty acyl-coenzyme As are inhibitors of cholesterol biosynthesis in zebrafish and mice

SUMMARYLipid disorders pose therapeutic challenges. Previously we discovered that mutation of the hepatocyte β-hydroxybutyrate transporter Slc16a6a in zebrafish causes hepatic steatosis during fasting, marked by increased hepatic triacylglycerol, but not cholesterol. This selective diversion of trapped ketogenic carbon atoms is surprising because acetate and acetoacetate can exit mitochondria and can be incorporated into both fatty acids and cholesterol in normal hepatocytes. To elucidate the mechanism of this selective diversion of carbon atoms to fatty acids, we fed wild-type and slc16a6a mutant animals high-protein ketogenic diets. We find that slc16a6a mutants have decreased activity of the rate-limiting enzyme of cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr), despite increased Hmgcr protein abundance and relative incorporation of mevalonate into cholesterol. These observations suggest the presence of an endogenous Hmgcr inhibitor. We took a candidate approach to identify such inhibitors. First, we found that mutant livers accumulate multiple polyunsaturated fatty acids (PUFAs) and PUFA-CoAs, and we showed that human HMGCR is inhibited by PUFA-CoAs in vitro. Second, we injected mice with an ethyl ester of the PUFA eicosapentaenoic acid and observed an acute decrease in hepatic Hmgcr activity, without alteration in Hmgcr protein abundance. These results elucidate a mechanism for PUFA-mediated cholesterol lowering through direct inhibition of Hmgcr.

Polyunsaturated fatty acids in multiple sclerosis therapy

Results from epidemiological and uncontrolled intervention studies in multiple sclerosis (MS) suggest a beneficial disease-modifying effect of increased intake of polyunsaturated fatty acids (PUFAs). To review the current evidence from animal studies and randomised controlled trials on the therapeutic effect of PUFAs in MS. We searched PubMed and Medline for articles using the terms 'polyunsaturated fatty acids', 'eicosapentaenoic acid', 'docosahexaenoic acid', 'linoleic acid', 'linolenic acid', 'omega-3' and 'omega-6' combined with 'multiple sclerosis', 'randomised controlled trials', 'animal models', 'experimental autoimmune encephalomyelitis' and 'cuprizone'. The abstracts of retrieved citations were reviewed and checked for relevant content. There was some evidence from animal model studies indicating an effect of ω-6 PUFAs, while the results from randomised controlled trials (RCTs) indicated that the ω-6 PUFAs linoleic acid or γ-linolenic acid have no beneficial effects on clinical disease activity in MS. However, the identified studies had several limitations in design with a mixture of relapsing-remitting and progressive MS patients. No studies investigated ω-6 efficacy on MRI disease activity. For ω-3 PUFAs, there was conflicting results from animal studies. RCTs show no beneficial treatment effect of the ω-3 PUFAs eicosapentaenoic acid and docosahexaenoic acid on MRI or clinical disease activity in MS. Randomised controlled trials of PUFA intervention provide no evidence of beneficial effects from ω-3 or ω-6 PUFAs on relapse rate, disability progression or MRI disease activity in MS.

OA04.02. Mechanisms of growth inhibition of pancreatic cancer by omega-3 polyunsaturated fatty acids

Purpose Omega-3 polyunsaturated fatty acids (PUFAs) are widely considered health promoting. We have previously reported that the omega-3 PUFA eicosapentaenoic acid (EPA) inhibits growth of pancreatic cancer (PaCa) cells in vitro and in vivo. However, the mechanism underlying the effects of EPA in PaCa cells is unknown. Methods

Fish, Fish-Derived n-3 Fatty Acids, and Risk of Incident Atrial Fibrillation in the Atherosclerosis Risk in Communities (ARIC) Study

BackgroundResults of observational and experimental studies investigating the association between intake of long-chain n-3 polyunsaturated fatty acids (PUFAs) and risk of atrial fibrillation (AF) have been inconsistent.MethodsWe studied the association of fish and the fish-derived n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) with the risk of incident AF in individuals aged 45–64 from the Atherosclerosis Risk in Communities (ARIC) cohort (n = 14,222, 27% African Americans). Intake of fish and of DHA and EPA were measured via food frequency questionnaire. Plasma levels of DHA and EPA were measured in phospholipids in a subset of participants (n = 3,757). Incident AF was identified through the end of 2008 using ECGs, hospital discharge codes and death certificates. Cox proportional hazards regression was used to estimate hazard ratios of AF by quartiles of n-3 PUFAs or by fish intake.ResultsDuring the average follow-up of 17.6 years, 1,604 AF events were identified. In multivariable analyses, total fish intake and dietary DHA and EPA were not associated with AF risk. Higher intake of oily fish and canned tuna was associated with a nonsignificant lower risk of AF (p for trend = 0.09). Phospholipid levels of DHA+EPA were not related to incident AF. However, DHA and EPA showed differential associations with AF risk when analyzed separately, with lower risk of AF in those with higher levels of DHA but no association between EPA levels and AF risk.ConclusionsIn this racially diverse sample, dietary intake of fish and fish-derived n-3 fatty acids, as well as plasma biomarkers of fish intake, were not associated with AF risk.

1256 DIETARY SUPPLEMENTATION WITH OLIVE OIL WITH OR WITHOUT N-3 PUFA DIFFERENTIALLY AFFECTS INFLAMMATION AND PROGRESSION OF EXPERIMENTAL NONALCOHOLIC STEATOHEPATITIS

Background/aims: While it is established that excessive calorie intake plays a role in the pathogenesis of nonalcoholic steatohepatitis, the significance of individual dietary factors is still elusive. Supplementation with n-3 polyunsaturated fatty acids (PUFA) has been shown to ameliorate fatty liver in experimental models, and clinical studies are underway. In this study we compared the effects of supplementation with olive oil (mostly composed of oleic acid, 18:1 n-9) or olive oil and n-3 PUFA on the progression of experimental steatohepatitis. Methods: Balb/C mice (≥5 mice/group) were fed a methionine and choline deficient (MCD) diet or a control diet for 4 or 8 weeks. At the same time, mice were supplemented with n-3 PUFA (eicosapentaenoic and docosahexahenoic acid, 25mg together with 75mg olive oil), or olive oil alone (OO, 100mg), two times a week by intragastric gavage Results: Aminotransferase levels were not different comparing mice supplemented with n-3 or OO after 4w of MCD diet, while after 8w mice on MCD/n-3 had more severe necroinflammation compared to MCD/OO (ALT: 373±170 vs. 87±29 UI/L, P < 0.05). Liver/body weight ratio was significantly lower in MCD/n-3 mice after 8w of treatment (5.1±0.8 vs. 6.8±1.0%, P< 0.05). At 8w, the score of inflammation and fibrosis was significantly higher in mice receiving MCD/n-3 than in MCD/OO animals, with a marked increase in the number of lipogranulomas (26.4±8.4 vs. 5.1±5. per field, P < 0.001). A significant increase in intrahepatic expression of TNF-alpha and CCL2 was observed at both 4w and 8w in MCD/n-3 mice, which also had increased expression of CD11b at 4 weeks. In addition, increased transcript levels of the profibrogenic genes TIMP-1 and TGF-beta, and lower expression of PPAR-alpha was observed in MCD/n-3 mice. After 8 week of MCD diet, portal pressure was higher in mice receiving n-3 than in those on OO (5.1±1.4 vs. 7.0±0.9mmHg, P < 0.05). No major differences were observed comparing n-3 and OO supplementation together with a control diet. Conclusions: In a model of steatohepatiits, supplementation with n-3 PUFA and OO is associated with more severe necroinflammation and fibrosis than in mice treated with OO only.

Antiapoptotic and Antiautophagic Effects of Eicosapentaenoic Acid in Cardiac Myoblasts Exposed to Palmitic Acid

Apoptosis is a programmed cell death that plays a critical role in cell homeostasis. In particular, apoptosis in cardiomyocytes is involved in several cardiovascular diseases including heart failure. Recently autophagy has emerged as an important modulator of programmed cell death pathway. Recent evidence indicates that saturated fatty acids induce cell death through apoptosis and this effect is specific for palmitate. On the other hand, n-3 polyunsaturated fatty acids (PUFAs) have been implicated in the protection against cardiovascular diseases, cardiac ischemic damage and myocardial dysfunction. In the present study we show that n-3 PUFA eicosapentaenoic acid (EPA) treatment to culture medium of H9c2 rat cardiomyoblasts protects cells against palmitate-induced apoptosis, as well as counteracts palmitate-mediated increase of autophagy. Further investigation is required to establish whether the antiautophagic effect of EPA may be involved in its cytoprotective outcome and to explore the underlying biochemical mechanisms through which palmitate and EPA control the fate of cardiac cells.

Temperature affects the limitation of Daphnia magna by eicosapentaenoic acid, and the fatty acid composition of body tissue and eggs

Summary 1. Poikilothermic animals incorporate more polyunsaturated fatty acids (PUFAs) into their cellular membranes as temperature declines, suggesting an increased sensitivity to PUFA limitation in cool conditions. To test this we raised Daphnia magna at different temperatures and investigated the effect of varying dietary PUFA on life history parameters (i.e. growth, reproduction) and the PUFA composition of body tissue and eggs. 2. Upon a PUFA-rich diet (Cryptomonas sp.) females showed higher concentrations of several ω3 PUFAs in their body tissue at 15 °C than at 20 °C and 25 °C, indicating a greater structural requirement for ω3 PUFAs at low temperature. Their eggs had an equal but higher concentration of ω3 PUFAs than their body tissue. 3. In a life history experiment at 15 and 20 °C we supplemented a diet of a PUFA-free cyanobacterium with the ω3 PUFA eicosapentaenoic acid (EPA). The growth of D. magna was more strongly EPA limited at low temperature. A greater requirement for structural EPA at 15 °C was indicated by a steeper increase in somatic EPA content with dietary EPA compared to 20 °C. 4. At 20 °C the development of eggs to successful hatching was high when EPA was supplied to the mothers. At 15 °C the hatching success was generally poor, despite of a higher maternal provision of EPA to eggs, compared to that at 20 °C, suggesting that EPA alone was insufficient for proper neonatal development at the low temperature. The growth of offspring from mothers raised at 20 °C without EPA supplementation was very low, indicating that the negative effects of EPA deficiency can be carried on to the next generation. 5. The fatty acid composition of Daphnia sp. in published field studies shows increasing proportions of saturated fatty acids with increasing environmental temperature, whereas ω3 PUFAs and EPA show no clear pattern, suggesting that variations in dietary PUFA may mask temperature-dependent adjustments in ω3 PUFA concentrations of cladocerans in nature.

Synovial Prostaglandin E2 Concentrations in Horses Fed Long Chain Polyunsaturated Fatty Acids: An Inquiry Study

Synovial Prostaglandin E2 Concentrations in Horses Fed Long Chain Polyunsaturated Fatty Acids: An Inquiry Study

Diversity of caecal bacteria is altered in interleukin-10 gene-deficient mice before and after colitis onset and when fed polyunsaturated fatty acids

Interleukin-10 gene-deficient (Il10(-/-)) mice show a hyper-reaction to normal intestinal bacteria and develop spontaneous colitis similar to that of human Crohn's disease when raised under conventional (but not germ-free) conditions. The lack of IL10 protein in these mice leads to changes in intestinal metabolic and signalling processes. The first aim of this study was to identify changes in the bacterial community of the caeca at 7 weeks of age (preclinical colitis) and at 12 weeks of age (when clinical signs of colitis are present), and establish if there were any changes that could be associated with the mouse genotype. We have previously shown that dietary n-3 and n-6 polyunsaturated fatty acids (PUFA) have anti-inflammatory effects and affect colonic gene expression profiles in Il10(-/-) mice; therefore, we also aimed to test the effect of the n-3 PUFA eicosapentaenoic acid (EPA) and the n-6 PUFA arachidonic acid (AA) on the bacterial community of caeca in both Il10(-/-) and C57 mice fed these diets. The lower number of caecal bacteria observed before colitis (7 weeks of age) in Il10(-/-) compared to C57 mice suggests differences in the intestinal bacteria that might be associated with the genotype, and this could contribute to the development of colitis in this mouse model. The number and diversity of caecal bacteria increased after the onset of colitis (12 weeks of age). The increase in caecal Escherichia coli numbers in both inflamed Il10(-/-) and healthy C57 mice might be attributed to the dietary PUFA (especially dietary AA), and thus not be a cause of colitis development. A possible protective effect of E. coli mediated by PUFA supplementation and associated changes in the bacterial environment could be a subject for further investigation to define the mode of action of PUFA in colitis.

Dietary supplementation with docosahexaenoic acid, but not eicosapentaenoic acid, dramatically alters cardiac mitochondrial phospholipid fatty acid composition and prevents permeability transition

Treatment with the ω-3 polyunsaturated fatty acids (PUFAs) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) exerts cardioprotective effects, and suppresses Ca 2+-induced opening of the mitochondrial permeability transition pore (MPTP). These effects are associated with increased DHA and EPA, and lower arachidonic acid (ARA) in cardiac phospholipids. While clinical studies suggest the triglyceride lowering effects of DHA and EPA are equivalent, little is known about the independent effects of DHA and EPA on mitochondria function. We compared the effects of dietary supplementation with the ω-3 PUFAs DHA and EPA on cardiac mitochondrial phospholipid fatty acid composition and Ca 2+-induced MPTP opening. Rats were fed a standard lab diet with either normal low levels of ω-3 PUFA, or DHA or EPA at 2.5% of energy intake for 8 weeks, and cardiac mitochondria were isolated and analyzed for Ca 2+-induced MPTP opening and phospholipid fatty acyl composition. DHA supplementation increased both DHA and EPA and decreased ARA in mitochondrial phospholipid, and significantly delayed MPTP opening as assessed by increased Ca 2+ retention capacity and decreased Ca 2+-induced mitochondria swelling. EPA supplementation increased EPA in mitochondrial phospholipids, but did not affect DHA, only modestly lowered ARA, and did not affect MPTP opening. In summary, dietary supplementation with DHA but not EPA, profoundly altered mitochondrial phospholipid fatty acid composition and delayed Ca 2+-induced MPTP opening.

Medaka as a model for human nonalcoholic steatohepatitis.

The global incidence of nonalcoholic steatohepatitis (NASH) is increasing and current mammalian models of NASH are imperfect. We have developed a NASH model in the ricefish medaka (Oryzias latipes), which is based on feeding the fish a high-fat diet (HFD). Medaka that are fed a HFD (HFD-medaka) exhibited hyperlipidemia and hyperglycemia, and histological examination of the liver revealed ballooning degeneration. The expression of lipogenic genes (SREBP-1c, FAS and ACC1) was increased, whereas the expression of lipolytic genes (PPARA and CPT1) was decreased. With respect to liver fatty acid composition, the concentrations of n-3 polyunsaturated fatty acids (PUFAs) and n-6 PUFAs had declined and the n-3:n-6 ratio was reduced. Treatment of HFD-medaka with the n-3 PUFA eicosapentaenoic acid (EPA) mitigated disease, as judged by the restoration of normal liver fatty acid composition and normal expression levels of lipogenic and lipolytic genes. Moreover, medaka that were fed a diet deficient in n-3 PUFAs developed NASH features. Thus, NASH can be induced in medaka by a HFD, and the proportion of n-3 PUFAs in the liver influences the progress of NASH pathology in these fish. Our model should prove helpful for the dissection of the causes of human NASH and for the design of new and effective therapies.