Dietary Docosahexaenoic Acid (DHA) and Eicosapentaenoic Acid (EPA) Operate by Different Mechanisms to Modulate Hepatic Steatosis and Hyperinsulemia in fa/fa Zucker Rats.
ABSTRACT: Hepatic steatosis, an early stage of non-alcoholic fatty liver disease, is commonly present in obesity and type 2 diabetes, and is associated with reduced hepatic omega-3 polyunsaturated fatty acid (n3-PUFA) status that impacts on the anti-inflammatory and insulin sensitizing functions of n3-PUFA. Our objective was to directly compare plant- and marine-based n3-PUFA (?-linoleic acid (ALA)), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA)) for their effects on hepatic steatosis, markers of hepatic inflammation and fibrosis, and insulinemia in obese rats. Fa/fa Zucker rats were provided diets containing ALA, EPA, DHA, or linoleic acid (LA, n6-PUFA) for eight weeks and compared to baseline fa/fa rats and lean Zucker rats fed LA-rich diet for eight weeks. Both DHA and EPA groups had liver lipid similar to baseline, however, DHA was more effective than EPA for reducing hepatic fatty acid synthase (FAS), increasing the proportion of smaller lipid droplets, reversing early fibrotic damage, and reducing fasting hyperinsulinemia. EPA was more effective for reducing FoxO1. Dietary ALA did not attenuate hepatic steatosis, most inflammatory markers or FAS. In summary, amongst the n3-PUFA, DHA was the most effective for elevating hepatic DHA levels, and preventing progression of hepatic steatosis via reductions in FAS and a marker of fibrosis.
Project description:Long chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) such as EPA and DHA have been shown to possess beneficial health effects, and it is believed that many of their effects are mediated by their oxygenated products (oxylipins). Recently, we have shown that serum levels of several hydroxy, epoxy, and dihydroxy FAs are dependent on the individual status of the parent FAs in a cohort of normo- and hyperlipidemic subjects. So far, the effect of an increased dietary LC n-3 PUFA intake on hydroxy, epoxy, and dihydroxy FA levels has not been investigated in subjects with mild combined hyperlipidemia.In the present study, we compared oxylipin patterns of 10 hyperlipidemic (cholesterol >200mg/dl; triglyceride >150mg/ml) and 10 normolipidemic men in response to twelve weeks of LC n-3 PUFA intake (1.14g DHA and 1.56g EPA). Levels of 44 free hydroxy, epoxy and dihydroxy FAs were analyzed in serum by LC-MS. Additionally, oxylipin levels were compared with their parent PUFA levels in erythrocyte membranes; a biomarker for the individual PUFA status.Differences in the oxylipin pattern between normo- and hyperlipidemic subjects were minor before and after treatment. In all subjects, levels of EPA-derived oxylipins (170-4800pM) were considerably elevated after LC n-3 PUFA intake (150-1400%), the increase of DHA-derived oxylipins (360-3900pM) was less pronounced (30-130%). The relative change of EPA in erythrocyte membranes is strongly correlated (r?0.5; p<0.05) with the relative change of corresponding epoxy and dihydroxy FA serum levels. The effect on arachidonic acid (AA)-derived oxylipin levels (140-27,100pM) was inconsistent.The dietary LC PUFA composition has a direct influence on the endogenous oxylipin profile, including several highly biological active EPA- and DHA-derived lipid mediators. The shift in oxylipin pattern appears to be dependent on the initial LC PUFA status particularly for EPA. The finding that also levels of other oxylipins derived from ALA, LA or AA are modified by LC n-3 PUFA intake might suggest that at least some of the effects of EPA and DHA could be mediated by a shift in the entire oxylipin profile.
Project description:The omega-3 (n3) polyunsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are associated with health benefits. The primary dietary source of EPA and DHA is seafood. Alpha-linoleic acid (ALA) has not been shown to be a good source for EPA and DHA; however, stearidonic acid (SDA)-which is naturally contained in echium oil (EO)-may be a more promising alternative. This study was aimed at investigating the short-term n3 PUFA metabolism after the ingestion of a single dose of EO. Healthy young male subjects (n = 12) ingested a single dose of 26 g of EO after overnight fasting. Plasma fatty acid concentrations and relative amounts were determined at baseline and 2, 4, 6, 8, 24, 48, and 72 h after the ingestion of EO. During the whole examination period, the participants received standardized nutrition. Plasma ALA and SDA concentrations increased rapidly after the single dose of EO. Additionally, EPA and DPAn3 concentrations both increased significantly by 47% after 72 h compared to baseline; DHA concentrations also significantly increased by 21% after 72 h. To conclude, EO increases plasma ALA, SDA, EPA, DPAn3, and DHA concentrations and may be an alternative source for these n3 PUFAs.
Project description:The replacement of fish oil (FO) and fishmeal with plant ingredients in the diet of farmed Atlantic salmon has resulted in reduced levels of the health-promoting long-chain polyunsaturated omega-3 fatty acids (n-3 LC-PUFA) eicosapentaenoic (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) in their filets. Previous studies showed the potential of selective breeding to increase n-3 LC-PUFA levels in salmon tissues, but knowledge on the genetic parameters for individual muscle fatty acids (FA) and their relationships with other traits is still lacking. Thus, we estimated genetic parameters for muscle content of individual FA, and their relationships with lipid deposition traits, muscle pigmentation, sea lice and pancreas disease in slaughter-sized Atlantic salmon. Our aim was to evaluate the selection potential for increased n-3 LC-PUFA content and provide insight into FA metabolism in Atlantic salmon muscle.Among the n-3 PUFA, proportional contents of alpha-linolenic acid (ALA; 18:3n-3) and DHA had the highest heritability (0.26) and EPA the lowest (0.09). Genetic correlations of EPA and DHA proportions with muscle fat differed considerably, 0.60 and 0.01, respectively. The genetic correlation of DHA proportion with visceral fat was positive and high (0.61), whereas that of EPA proportion with lice density was negative. FA that are in close proximity along the bioconversion pathway showed positive correlations with each other, whereas the start (ALA) and end-point (DHA) of the pathway were negatively correlated (-?0.28), indicating active bioconversion of ALA to DHA in the muscle of fish fed high FO-diet.Since contents of individual FA in salmon muscle show additive genetic variation, changing FA composition by selective breeding is possible. Taken together, our results show that the heritabilities of individual n-3 LC-PUFA and their genetic correlations with other traits vary, which indicates that they play different roles in muscle lipid metabolism, and that proportional muscle contents of EPA and DHA are linked to body fat deposition. Thus, different selection strategies can be applied in order to increase the content of healthy omega-3 FAin the salmon muscle. We recommend selection for the proportion of EPA?+?DHA in the muscle because they are both essential FA and because such selection has no clear detrimental effects on other traits.
Project description:It is believed that many of the beneficial effects of long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) are mediated by their oxidized metabolites, the oxylipins. The formation and biological role of many cytochrome P450 and lipoxygenase derived hydroxy, epoxy and dihydroxy FA, particularly of oxylipins esterified in polar lipids and triglycerides remain unclear. In this study, we compared the impact of twelve weeks of LC n-3 PUFA supplementation on the patterns of free and total (sum of esterified and free) hydroxy, epoxy and dihydroxy FAs.Subjects (5 male; 5 female) between 46 and 70 years were supplemented with 1.1g/d of eicosapentaenoic acid (EPA) and 0.74g/d docosahexaenoic acid (DHA) as ethyl esters. Blood samples were drawn before and after twelve weeks of treatment. Oxylipins in plasma were analyzed by LC-MS directly for free oxylipins and after saponification. Relative FA composition in erythrocyte membranes was analyzed by GC.LC n-3 PUFA treatment led to a significant increase in EPA (200%) and DHA (23%) in erythrocyte membranes. Of the oxylipins measured in plasma, total and free EPA-derived metabolites were highly increased (70-150%), while total AA-derived metabolites were decreased on average by 30%. There was no effect on DHA-metabolites. Concentrations of total hydroxy and epoxy FAs in plasma were considerably higher compared to free hydroxy and epoxy FAs (up to 350 times), while levels of most free dihydroxy FAs were in a similar range to total dihydroxy FAs. However, the individual ratios between total and free plasma oxylipins remained unchanged after LC n-3 PUFA treatment.LC n-3 PUFA supplementation causes a shift in the levels of circulating oxylipins, having the strongest impact on EPA-derived epoxy, dihydroxy and hydroxy FA. The unchanged ratio of free and esterified oxylipins in plasma indicates that both concentrations are valuable biomarkers for assessing the individual status of these lipid mediators.
Project description:Dietary intervention and genetic fat-1 mice are two models for the investigation of effects associated with omega-3 polyunsaturated fatty acids (n3-PUFA). In order to assess their power to modulate the fatty acid and oxylipin pattern, we thoroughly compared fat-1 and wild-type C57BL/6 mice on a sunflower oil diet with wild-type mice on the same diet enriched with 1% EPA and 1% DHA for 0, 7, 14, 30 and 45 days. Feeding led after 14-30 days to a high steady state of n3-PUFA in all tissues at the expense of n6-PUFAs. Levels of n3-PUFA achieved by feeding were higher compared to fat-1 mice, particularly for EPA (max. 1.7% in whole blood of fat-1 vs. 7.8% following feeding). Changes in PUFAs were reflected in most oxylipins in plasma, brain and colon: Compared to wild-type mice on a standard diet, arachidonic acid metabolites were overall decreased while EPA and DHA oxylipins increased with feeding more than in fat-1 mice. In plasma of n3-PUFA fed animals, EPA and DHA metabolites from the lipoxygenase and cytochrome P450 pathways dominated over ARA derived counterparts.Fat-1 mice show n3-PUFA level which can be reached by dietary interventions, supporting the applicability of this model in n3-PUFA research. However, for specific questions, e.g. the role of EPA derived mediators or concentration dependent effects of (individual) PUFA, feeding studies are necessary.
Project description:Numerous genetic loci have been identified as being associated with circulating fatty acid (FA) levels and/or inflammatory biomarkers of cardiovascular health (e.g., C-reactive protein). Recently, using red blood cell (RBC) FA data from the Framingham Offspring Study, we conducted a genome-wide association study of over 2.5 million single nucleotide polymorphisms (SNPs) and 22 RBC FAs (and associated ratios), including the four Omega-3 FAs (ALA, DHA, DPA, and EPA). Our analyses identified numerous causal loci. In this manuscript, we investigate the extent to which polyunsaturated fatty acid (PUFA) levels moderate the relationship of genetics to cardiovascular health biomarkers using a genome-wide interaction study approach. In particular, we test for possible gene-FA interactions on 9 inflammatory biomarkers, with 2.5 million SNPs and 12 FAs, including all Omega-3 PUFAs. We identified eighteen novel loci, including loci which demonstrate strong evidence of modifying the impact of heritable genetics on biomarker levels, and subsequently cardiovascular health. The identified genes provide increased clarity on the biological functioning and role of Omega-3 PUFAs, as well as other common fatty acids, in cardiovascular health, and suggest numerous candidate loci for future replication and biological characterization.
Project description:The omega-3 fatty acid (n-3 FA) eicosapentaenoic acid (EPA) reduces stroke in patients with atherosclerotic cardiovascular disease. Whether EPA affects stroke or cerebral small vessel dis-ease in patients with atrial fibrillation (AF) remains uncertain. EPA, docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), and alpha-linolenic acid (ALA) were determined by gas chromatography in 1657 AF patients from the Swiss Atrial Fibrillation study. All patients underwent brain MRI to detect ischemic brain infarcts, classified as large noncortical or cortical infarcts (LNCCIs); markers of small vessel disease, classified as small noncortical infarcts (SNCIs), number of microbleeds, and white matter lesion (WML) volumes. Individual and total n-3 FAs (EPA + DHA + DPA + ALA) were correlated with LNCCIs and SNCIs using logistic regression, with numbers of microbleeds using a hurdle model, and WML volumes using linear regression. LNCCIs were detected in 372 patients (22.5%). EPA correlated inversely with the prevalence of LNCCIs (odds ratio [OR] 0.51 per increase of 1 percentage point EPA, 95% confidence interval [CI] 0.29-0.90). DPA correlated with a higher LNCCI prevalence (OR 2.48, 95%CI 1.49-4.13). No associations with LNCCIs were found for DHA, ALA, and total n-3 FAs. Neither individual nor total n-3 FAs correlated with markers of small vessel disease. In conclusion, EPA correlates inversely with the prevalence of ischemic brain infarcts, but not with markers of small vessel disease in patients with AF.
Project description:Evidence regarding the relationship of n-3 fatty acids (FA) to type 2 diabetes and metabolic syndrome components (MetS) is inconsistent.To examine associations of adipose tissue n-3 FA with MetS.We studied 1611 participants without prior history of diabetes or heart disease who were participants in a population-based case-control study of diet and heart disease (The Costa Rica Heart Study). We calculated prevalence ratios (PR) and 95% confidence intervals (CI) for MetS by quartile of n-3 FA in adipose tissue derived mainly from plants (?-Linolenic acid (ALA)), fish (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) or metabolism (docosapentaenoic acid (DPA), as well as the EPA:ALA ratio, a surrogate marker of delta-6 desaturase activity).N-3 FA levels in adipose tissue were associated with MetS prevalence in opposite directions. The PR (95% CI) for the highest compared with the lowest quartile adjusted for age, sex, body mass index (BMI), residence, lifestyle, diet and other FAs were 0.60 (0.44, 0.81) for ALA, 1.43 (1.12, 1.82) for EPA, 1.63 (1.22, 2.18) for DPA and 1.47 (1.14, 1.88) for EPA:ALA, all P for trend <0.05. Although these associations were no longer significant (except DPA) after adjustment for BMI, ALA and DPA were associated with lower glucose and higher triglyceride levels, P<0.05 (respectively).These results suggest that ALA could exert a modest protective benefit, whereas EPA and DHA are not implicated in MetS. The positive associations for DPA and MetS could reflect higher delta-6 desaturase activity caused by increased adiposity.
Project description:BACKGROUND AND AIMS:Population-based studies often use plasma fatty acids (FAs) as objective indicators of FA intake, especially for n-3 FA and linoleic acid (LA). The relation between dietary and circulating FA in cardiometabolic patients is largely unknown. We examined whether dietary n-3 FA and LA were reflected in plasma lipid pools in post-myocardial infarction (MI) patients. METHODS AND RESULTS:Patients in Alpha Omega Cohort filled out a 203-item food-frequency questionnaire from which eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), and LA intake were calculated. Circulating individual FA (% total FA) were assessed in cholesteryl esters (CE; n = 4066), phospholipids (PL; n = 838), and additionally in total plasma for DHA and LA (n = 739). Spearman correlation coefficients (rs) were calculated for dietary vs. circulating FA. Circulating FA were also compared across dietary FA quintiles, overall and in subgroups by sex, obesity, diabetes, statin use, and high alcohol intake. Patients were on average 69 years old and 79% was male. Moderate correlations between dietary and circulating levels were observed for EPA (rs?0.4 in CE and PL) and DHA (rs ?0.5 in CE and PL, ?0.4 in total plasma), but not for ALA (rs ?0.0). Weak correlations were observed for LA (rs 0.1 to 0.2). Plasma LA was significantly lower in statin users and in patients with a high alcohol intake. CONCLUSIONS:In post-MI patients, dietary EPA and DHA were well reflected in circulating levels. This was not the case for LA, which may partly be influenced by alcohol use and statins.
Project description:Finding new alternatives to traditional live preys such as Artemia and rotifers, which do not always promote optimal fish growth and survival, is required for the successful aquaculture of highly specialized predatory species, including seahorses. The present study assessed the nutritional value of an interesting marine amphipod (Parhyale hawaiensis), and evaluates through a feeding trial its potential use as a natural prey for 10-months lined seahorse, Hippocampus erectus. P. hawaiensis showed high levels of valuable lipids (20.4–26.7% on dry matter basis) and polyunsaturated fatty acids (PUFAs) ( 26.4–41% of total FAs), including the long-chain PUFAs (LC-PUFAs) arachidonic acid (ARA) (2.9–7.7%), eicosapentaenoic acid (EPA) (4.3–6.5%) and docosahexaenoic acid (DHA) (2.1–6.2%). A comparison between wild-captured and cultured amphipods revealed a significant improvement of the amphipod FA profile in terms of DHA%, total omega-3 (n3) FAs and n3/n6 ratio when employing both a conventional amphipod culture based on a commercial shrimp diet, and, to a lesser extent, a large (3,500 L) biofloc system. Seahorses fed with frozen/wild amphipods, either singly or in combination with Artemia enriched with Super Selco® (INVE Aquaculture, Belgium) for 57 days, substantially improved seahorse growth and FA profiles in terms of ARA, EPA and DHA%, including indices associated to marine sources, such as Σn3 and n3/n6, compared to a diet based solely on enriched Artemia. These results support the use of marine amphipods as an alternative food organism for juvenile H. erectus and suggest a potential use for general marine aquaculture.