ω-3 polyunsaturated fatty acids and the cardiovascular system

ω-3 polyunsaturated fatty acids (PUFAs) (alpha-linolenic, eicosapentaenoic, and decosahexaenoic acids) are classified with essential fatty acids and are structural components of the phospholipid bilayer of cell membranes. ω-3 PUFAs incorporated into the phospholipid domain of cell membranes are metabolized to prostaglandins and thromboxanes (PGI ₃, PGE ₃, TxA, etc.), which significantly differ in biological activity from those formed in the arachidonic acid cascade (PGI ₂, PGE ₂, TxA ₂, etc.) and to which the antiaggregatory, antiatherogenic, and vasodilating effects of ω-3 PUFAs can largely be attributed. In addition, ω-3 PUFAs incorporated into cardiomyocyte cell membranes considerably modify the functional activity of transmembrane voltage-gated ion channels by causing a dose-dependent inhibition of the outward transmembrane sodium current, slowing down the work of transmembrane voltage-gated slow L-type calcium channels, and partially blocking the efflux of potassium ions from cardiomyocytes, thus showing the properties of class I, III, and IV antiarrhythmic drugs according to the Vaughnan Williams classification. Several clinical trials have supported experimental data that ω-3 PUFAs have membrane-stabilizing (antiarrhythmogenic) effects. For example, in the GISSI-Prevenzione trial, a large-scale, randomized, placebo-controlled study conducted in more than 9.5 thousand patients with left ventricular systolic dysfunction after myocardial infarction, ω-3 PUFA regular consumption significantly reduced the risk of sudden cardiac death by more than 50% in these patients. In our review, the mechanisms underlying the membrane-stabilizing, antiaggregatory, antiatherogenic, and vasodilating effects of ω-3 PUFAs and the clinical effectiveness of ω-3 PUFAs have been analyzed in terms of evidencebased pharmacology.     

n−3 polyunsaturated fatty acids modulate metabolism of insulin-sensitive tissues: implication for the prevention of type 2 diabetes

Obesity is frequently associated with the development of type 2 diabetes which is firstly characterized by a defect in the response of key metabolic tissues to insulin (insulin resistance). The imbalance in fatty composition of the diet, a low-grade inflammatory state have been described to be involved in the initiation or the amplification of the molecular events involved in this process. The concept of a specific nutritional intervention has emerged as a promising tool against metabolic disorders associated with obesity. In this context, many investigations were conducted to evaluate the potential beneficial impacts of n?3 polyunsaturated fatty acids (n?3 PUFA). The aim of the present review was to summarize the current knowledge about the role of docosahexanoic acid (DHA, 22:6n?3) and eicosapentanoic acid (EPA, 20:5n?3) on key metabolic organs. Only studies aiming to understand the mechanism of actions were selected. The analysis of randomized clinical trial about n?3 PUFA was not considered here. The effects of n?3 PUFA were analyzed in the adipose tissue, the liver, skeletal muscle and the pancreas in the context of obesity and lipid oversupply. Furthermore, in line with recent findings about the role of the modulation of gut microbiota in obesity-related disorders, we summarized the recent findings about the possible link between n?3 PUFA and change in microbiota composition.     

Cimicifuga racemosa impairs fatty acid β-oxidation and induces oxidative stress in livers of ovariectomized rats with renovascular hypertension

The aim of this work was to evaluate the effects of therapeutic doses of Cimicifuga racemosa on cardiovascular parameters and on liver lipid metabolism and redox status in an animal model of estrogen deficiency associated with hypertension, a condition that could make the liver more vulnerable to drug-induced injuries. Female Wistar rats were subjected to the surgical procedures of bilateral ovariectomy (OVX) and induction of renovascular hypertension (two-kidneys, one-clip; 2K1C). These animals (OVX + 2K1C) were treated with daily doses of a C. racemosa extract, using a dose that is similar to that recommended to postmenopausal women (0.6mg/kg), over a period of 15 days. The results were compared to those of untreated OVX + 2K1C, OVX, and control rats. The treatment with C. racemosa caused a significant reduction in blood pressure. In the liver, treatment did not prevent the development of steatosis, and it reduced the mitochondrial and peroxisomal capacity to oxidize octanoyl-CoA compared to the untreated animals. In addition, C. racemosa caused numerous undesirable effects on the liver redox status: it increased the mitochondrial reactive oxygen species generation, an event that was not accompanied by an increase in the activity of superoxide dismutase, and it induced a decrease in peroxisomal catalase activity. Although the reduced glutathione content had not been affected, a phenomenon that probably reflected the restoration of glucose-6-phosphate dehydrogenase activity by C. racemosa, oxidative damage was evidenced by the elevated level of thiobarbituric acid-reactive substances found in the liver of treated animals.     

The role of Δ6-desaturase acyl-carrier specificity in the efficient synthesis of long-chain polyunsaturated fatty acids in transgenic plants

The role of acyl‐CoA‐dependent Δ6‐desaturation in the heterologous synthesis of omega‐3 long‐chain polyunsaturated fatty acids was systematically evaluated in transgenic yeast and Arabidopsis thaliana. The acyl‐CoA Δ6‐desaturase from the picoalga Ostreococcus tauri and orthologous activities from mouse (Mus musculus) and salmon (Salmo salar) were shown to generate substantial levels of Δ6‐desaturated acyl‐CoAs, in contrast to the phospholipid‐dependent Δ6‐desaturases from higher plants that failed to modify this metabolic pool. Transgenic plants expressing the acyl‐CoA Δ6‐desaturases from either O. tauri or salmon, in conjunction with the two additional activities required for the synthesis of C20 polyunsaturated fatty acids, contained higher levels of eicosapentaenoic acid compared with plants expressing the borage phospholipid‐dependent Δ6‐desaturase. The use of acyl‐CoA‐dependent Δ6‐desaturases almost completely abolished the accumulation of unwanted biosynthetic intermediates such as γ‐linolenic acid in total seed lipids. Expression of acyl‐CoA Δ6‐desaturases resulted in increased distribution of long‐chain polyunsaturated fatty acids in the polar lipids of transgenic plants, reflecting the larger substrate pool available for acylation by enzymes of the Kennedy pathway. Expression of the O. tauriΔ6‐desaturase in transgenic Camelina sativa plants also resulted in the accumulation of high levels of Δ6‐desaturated fatty acids. This study provides evidence for the efficacy of using acyl‐CoA‐dependent Δ6‐desaturases in the efficient metabolic engineering of transgenic plants with high value traits such as the synthesis of omega‐3 LC‐PUFAs.     

Absorption and metabolism of short‐chain fatty acids in ruminants

Short‐chain fatty acids (SCFA), viz. acetate, propionate and butyrate are quantitatively important substrates in ruminant energy metabolism. In the reviewed literature, 16–44% of ME intake was recovered as portal appearance of SCFA. This is considerably lower than expected when related to the estimated intra‐gastric flux of SCFA. The discrepancy is caused by portal drained viscera metabolism of arterially abundant metabolites e.g., acetate and the metabolism of acetate and butyrate to acetoacetate and D‐3‐hydroxybu‐tyrate in the absorptive epithelia. Even though considerable variations between experiments on acetate and propionate appearance are found, there seems to be a great deal of evidence that the proportion of gastroin‐testinally produced acetate and propionate absorbed to the portal blood is 50–75%. The portal recovery of butyrate has been found to be between 10 and 36% dependent on intraruminal infusion rate.

It is concluded that major parts of acetate and propionate are directly absorbed to the portal vein. The true absorption rate of acetate can only be estimated by taking the portal drained viscera metabolism of arterial actetate into account. Butyrate is generally found to have a low recovery in the portal vein, but the production of D‐3‐hydroxybutyrate seems to be underestimated in major parts of the literature. It is therefore necessary to measure portal appearance as well as portal drained viscera metabolism to assess the quantitative as well as the qualitative contribution of SCFA and SCFA metabolites to whole animal metabolism.     

Chemical synthesis and biological evaluation of ω-hydroxy polyunsaturated fatty acids

ω-Hydroxy polyunsaturated fatty acids (PUFAs), natural metabolites from arachidonic acid (ARA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were prepared via convergent synthesis approach using two key steps: Cu-mediated CC bond formation to construct methylene skipped poly-ynes and a partial alkyne hydrogenation where the presence of excess 2-methyl-2-butene as an additive that is proven to be critical for the success of partial reduction of the poly-ynes to the corresponding cis-alkenes without over-hydrogenation. The potential biological function of ω-hydroxy PUFAs in pain was evaluated in naive rats. Following intraplantar injection, 20-hydroxyeicosatetraenoic acid (20-HETE, ω-hydroxy ARA) generated an acute decrease in paw withdrawal thresholds in a mechanical nociceptive assay indicating pain, but no change was observed from rats which received either 20-hydroxyeicosapentaenoic acid (20-HEPE, ω-hydroxy EPA) or 22-hydroxydocosahexaenoic acid (22-HDoHE, ω-hydroxy DHA). We also found that both 20-HEPE and 22-HDoHE are more potent than 20-HETE to activate murine transient receptor potential vanilloid receptor1 (mTRPV1).     

The role of omega-3 polyunsaturated fatty acids eicosapentaenoic and docosahexaenoic acids in the treatment of major depression and Alzheimer's disease: Acting separately or synergistically?

Omega-3 polyunsaturated fatty acids (n‐3-PUFAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may improve or prevent some psychiatric and neurodegenerative diseases in both experimental and clinical studies. As important membrane components, these PUFAs benefit brain health by modulating neuroimmune and apoptotic pathways, changing membrane function and/or competing with n‐6 PUFAs, the precursors of inflammatory mediators. However, the exact role of each fatty acid in neuroimmune modulation and neurogenesis, the interaction between EPA and DHA, and the best EPA:DHA ratios for improving brain disorders, remain unclear. It is also unknown whether EPA, as a DHA precursor, acts directly or via DHA. Here, we discuss recent evidence of EPA and DHA effects in the treatment of major depression and Alzheimer's disease, as well as their potential synergistic action on anti-inflammatory, antioxidant and neurotrophic processes in the brain. We further analyze the cellular and molecular mechanisms by which EPA, DHA or their combination may benefit these diseases. We also outline the limitations of current studies and suggest new genetic models and novel approaches to overcome these limitations. Finally, we summarize future strategies for translational research in this field.     

α-Linolenic acid supplementation and conversion to n-3 long-chain polyunsaturated fatty acids in humans

Blood levels of polyunsaturated fatty acids (PUFA) are considered biomarkers of status. Alpha-linolenic acid, ALA, the plant omega-3, is the dietary precursor for the long-chain omega-3 PUFA eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA). Studies in normal healthy adults consuming western diets, which are rich in linoleic acid (LA), show that supplemental ALA raises EPA and DPA status in the blood and in breast milk. However, ALA or EPA dietary supplements have little effect on blood or breast milk DHA levels, whereas consumption of preformed DHA is effective in raising blood DHA levels. Addition of ALA to the diets of formula-fed infants does raise DHA, but no level of ALA tested raises DHA to levels achievable with preformed DHA at intakes similar to typical human milk DHA supply. The DHA status of infants and adults consuming preformed DHA in their diets is, on average, greater than that of people who do not consume DHA. With no other changes in diet, improvement of blood DHA status can be achieved with dietary supplements of preformed DHA, but not with supplementation of ALA, EPA, or other precursors.     

Role of ω-3 fatty acid desaturases in the regulation of the level of trienoic fatty acids during leaf cell maturation

Trienoic fatty acids, namely -linolenic acid and hexadecatrienoic acid, present in leaf lipids are produced by -3 fatty acid desaturases located in the endoplasmic reticulum and plastid membranes. The changes in the level of trienoic fatty acids during leaf maturation were investigated in wild-type plants of Arabidopsis thaliana (L.) Heynh. and in the fad7 mutant deficient in the activity of a plastid -3 desaturase. The levels of trienoic fatty acids increased in 26 °C- and 15 °C-grown wild-type plants with maturation of leaves. The increase in trienoic fatty acids was mainly due to galactolipids enriched in plastid membranes. In addition, the relative levels of trienoic fatty acids in major glycerolipids, including phospholipids enriched in the endoplasmic reticulum membranes, also increased with leaf maturation. By contrast, when the fad7 mutant was grown at 26 °C, the relative levels of trienoic fatty acids in individual lipids decreased with leaf maturation. The decreases in the levels of trienoic fatty acids, however, were alleviated when the fad7 mutant was grown at 15 °C. These results suggest that the plastid -3 desaturase plays a major role in increasing the levels of trienoic fatty acids with leaf maturation.Abbreviations 163 hexadecatrienoic acid - 183 -linolenic acid - DGD digalactosyldiacylglycerol - MGD monogalactosyldiacylglycerol - PC phosphatidylcholine - PE phosphatidylethanolamine - TA trienoic fatty acid - WT wild type - -3 refers to the position of the double bond from the methyl end of a fatty acid This research was supported in part by Grants-in-Aid for Scientific research (#07251214 and #06804050 to K.I.) from the Ministry of Education, Science and Culture, Japan, and by the research grant from Shorai Foundation.     

Ameliorative effects of ω-3 fatty acids on stress induced alteration in rhythms of selective biochemical parameters in rats

Twenty-four adult male Sprague-Dawley rats were randomly divided into four groups of six rats in each, Control animals without stress (GI); Rats with induced physical stress (GII); Normal Rats fed with omega fish oil as a source of omega-3 fatty acid (GIII); Stressed Rats supplemented omega-3 fatty acid diet (GIV). In GII and GIV physical stress was induced by keeping six rats in a standard cage instead of four rats and in GIV fish oil was added in the feed @ 3% to ameliorate the physical stress. Sampling was done on 15th and 29th day of the study. On 15th day of study no significant difference was found between the groups with respect to blood glucose and total protein levels, but on 29th day there was significant increase in blood glucose in GII and significant decrease in GIII. There was significant increase in total protein of GIII and decrease in GII, respectively apart from the significant increase in GIII on 29th day as compared to 15th day. Serum creatinine levels were found to be significantly lower in both the samples of GIII. The total and LDL cholesterol was significantly higher in GII but on 29th day it was found to be significantly lower in GIII. The HDL cholesterol was significantly lower in GII and significantly higher in GIII on 29th day, whereas it was vice versa with respect to triglycerides. Serum ALT, was found to be significantly lower in GIII and higher in GII on 29th day with no significant changes observed on 15th day. The liver of GII revealed central vein congestion and mononuclear cell infiltration in portal triad, whereas GIV showed only mild changes. The study proves the time-dependent beneficial effects of omega-3 fatty acids during physical stress.     

Omega-3 fatty acids in cancer, the protectors of good and the killers of evil?

Omega-3 fatty acids have been implicated in cancer prevention and treatment. Conventional chemotherapeutics are considered “double-edged swords”, as they kill the cancer cells but also strike the healthy cells causing severe morbidity and sometimes also mortality. Could omega-3 fatty acids in this setting work as a “sword and shield” instead, by being cytotoxic to cancer cells, but at the same time protect healthy cells from these deleterious effects? In addition, may our current diet with decreased omega-3/omega-6 ratio contribute to the increased cancer incidence, and could an omega-3 enriched diet be used as a preventive measure against cancer?Here, we seek answers to these questions by reviewing the effects of omega-3 fatty acids, particularly DHA, on various cancers with emphasis on a cancer of neural origin, neuroblastoma. Results from preventive and therapeutic animal as well as human studies together with mechanisms behind the observed toxicity are summarized.     

Is administration of n-3 fatty acids by mucosal enema protective against trinitrobenzene-induced colitis in rats?

We investigated the protective role of fish oil (FO-source of n-3 FA) enriched diet (in the first protocol) in 20 rats and FO administration intrarectally (in the second protocol) in 40 rats with trinitrobenzene (TNB) colitis. All colonic specimens were pathologically evaluated, myeloperoxidase enzyme activities were measured, leukotriene B4 (LTB4) and LTC4 levels were determined by radioimmunoassay. In the first protocol 10 rats (group A1) were fed with 8% sunflower and cotton oil enriched diet and (group A2) with 8% FO enriched diet for 6 weeks. At the end of this period, TNB (30 mg in 0.25 ml of 30% ethanol) were intrarectally administered. After 2 weeks, rats were sacrificed. MPO activities (2.47 versus 30.17), LTB4 (34.5 versus 903.3) and LTC4 (77.7 versus 456.0) levels were significantly reduced in group A2 compared with group A1 (P<0.005). There was also a significant difference in pathologic scores (1.55 versus 2.12, P<0.002) between two groups. In the first part of the second protocol, 20 male rats were randomized into two equal groups (B1 and B2) and TNB colitis was induced. After 1 day, 1 ml of saline (group B1) or n-3 FA enemas (group B2) were administered every day for 2 weeks. At the end of this period, rats were sacrificed and evaluated as done for previous groups. Although there was no significant difference between the two groups in comparison with MPO enzyme activities and pathologic scores, the LTB4 (130.1 versus 971.0) and LTC4 (126.0 versus 532.0) levels of FO group were significantly reduced (P<0.005). In the second part of the second protocol, 20 male rats were randomized into two groups. One millilitre of saline (group B3) or FO enemas (group B4) were administered to rats every day for 3 days. At the fourth day, TNB-colitis was induced and after 24 h rats were sacrificed. We could not find any significant difference in MPO activities, pathologic scores, LTB4 and LTC4 levels between groups B3 and B4. In conclusion, FO enriched diet decreased both pathologic damage and tissue LT levels. The second protocol of our study revealed that the long-term FO enemas decreased the LTB4 and LTC4 levels; however, did not have any beneficial effect on the tissue lesions. Short periods of FO enemas did not have a protective role in the occurrence of experimental colitis. The present study showed that FO enemas significantly decreased LT levels. The protective effect of FO (oral and enema) in TNB colitis may open a new insight into the treatment of inflammatory bowel disease.     

Partial rescue of Rett syndrome by ω-3 polyunsaturated fatty acids (PUFAs) oil

Evidence of enhanced oxidative stress (O.S.) and lipid peroxidation has been reported in patients with Rett syndrome (RTT), a relatively rare neurodevelopmental disorder progressing in 4-stages, and mainly caused by loss-of-function mutations in the methyl-CpG-binding protein 2. No effective therapy for preventing or arresting the neurologic regression in the disease in its various clinical presentations is available. Based on our prior evidence of enhanced O.S. and lipid peroxidation in RTT patients, herein we tested the possible therapeutic effects of ω-3 polyunsaturated fatty acids (ω-3 PUFAs), known antioxidants with multiple effects, on the clinical symptoms and O.S. biomarkers in the earliest stage of RTT. A total of 20 patients in stage I were randomized (n = 10 subjects per arm) to either oral supplementation with ω-3 PUFAs-containing fish oil (DHA: 72.9 ± 8.1 mg/kg b.w./day; EPA: 117.1 ± 13.1 mg/kg b.w./day; total ω-3 PUFAs: 246.0 ± 27.5 mg/kg b.w./day) for 6 months or no treatment. Primary outcomes were potential changes in clinical symptoms, with secondary outcomes including variations for five O.S. markers in plasma and/or erythrocytes (nonprotein bound iron, F₂-dihomo-isoprostanes, F₃-isoprostanes, F₄-neuroprostanes, and F₂-isoprostanes). A significant reduction in the clinical severity (in particular, motor-related signs, nonverbal communication deficits, and breathing abnormalities) together with a significant decrease in all the examined O.S. markers was observed in the ω-3 PUFAs supplemented patients, whereas no significant changes were evidenced in the untreated group. For the first time, these findings strongly suggest that a dietary intervention in this genetic disease at an early stage of its natural history can lead to a partial clinical and biochemical rescue.

Electronic supplementary material

The online version of this article (doi:10.1007/s12263-012-0285-7) contains supplementary material, which is available to authorized users.     

Could n-3 polyunsaturated fatty acids reduce pathological pain by direct actions on the nervous system?

The intake of n-3 polyunsaturated fatty acids (PUFAs) in many industrialized countries is relatively low and its increased consumption has protective and modifying effects on such diverse conditions as atherosclerosis, ventricular arrhythmias, multiple sclerosis, major depression and inflammatory and autoimmune diseases. In addition, n-3 PUFAs have been shown to alleviate pain in patients with rheumatoid arthritis, inflammatory bowel disease and in a number of other painful conditions. This has been attributed to the inhibition of pro-inflammatory eicosanoid and cytokine production by peripheral tissues. n-3 PUFAs have also been shown to inhibit eicosanoid production in glial cells, block voltage-gated sodium channels (VGSCs), inhibit neuronal protein kinases and modulate gene expression. They also appear to have mood-stabilizing and sympatholytic effects. The present article explores the possibility that, based on what is known about their neural and non-neural effects, n-3 PUFAs directly attenuate the neuronal and glial processes that underlie neuropathic and inflammatory pain.     

Higher de novo synthesized fatty acids and lower ω3- and ω6-long-chain polyunsaturated fatty acids in umbilical vessels of women with preeclampsia and high fish intakes

Umbilical veins (UV) and arteries (UA) of preeclamptic women in Curaçao harbor lower long-chain polyunsaturated fatty acids (LCP). The present aim was to test these findings in Mwanza (Tanzania), whose inhabitants have high LCPω3 and LCPω6 intakes from Lake Victoria fish. Women with preeclampsia (n=28) in Mwanza had lower PUFA and higher 20:0 in UV and UA, compared with normotensive/non-proteinuric controls (n=31). Their UV 22:6ω3, 22:4ω6, LCPω6, ω6, and LCPω3+ω6 were lower, while saturated FA, potentially de novo synthesized FA (Σde novo) and (Σde novo)/(LCPω3+ω6) ratio were higher. Their UA had higher 16:1ω7, ω7, 18:0, and 16:1ω7/16:0. Umbilical vessels in Mwanza had higher 22:6ω3, LCPω3, ω3, and 16:0, and lower 22:5ω6, 20:2ω6, 18:1ω9, and ω9, compared to those in Curaçao. Preeclampsia in both Mwanza and Curaçao is characterized by lower LCP and higher Σde novo. An explanation of this might be placental dysfunction, while the similarity of umbilical vessel FA-abnormalities in preeclamptic and diabetic pregnancies suggests insulin resistance as a common denominator.     

Dietary monounsaturated versus polyunsaturated fatty acids: which is really better for protection from coronary heart disease?

PURPOSE OF REVIEW: The purpose is to evaluate recent findings concerning dietary fats and the risk of coronary heart disease. Monounsaturated fatty acids are often regarded as healthy, and many have recommended their consumption instead of saturated fatty acids and polyunsaturated fatty acids. Support for the benefits of monounsaturated fatty acids comes largely from epidemiological data, but they have not been an isolated, single variable in such studies. Beneficial effects on the plasma lipid profile and LDL oxidation rates have also been identified. More recent findings have questioned the impact of suspected beneficial effects on coronary heart disease, indicating that studies with more conclusive endpoints are needed. RECENT FINDINGS: Human dietary studies often produce conflicting results regarding the effects of monounsaturated and polyunsaturated fatty acids on the plasma lipid profile. Monounsaturated and polyunsaturated fatty acids both appear to reduce total and LDL-cholesterol compared with saturated fatty acids; however, the effect on HDL is less clear. Lowered HDL levels in response to low-fat or polyunsaturated fatty acid diets and the decreased protection from oxidation of polyunsaturated fatty acid-enriched LDL may not indicate increased coronary heart disease risk. Several lines of evidence also suggest that polyunsaturated fatty acids may protect against atherosclerosis. SUMMARY: Recommendations to substitute monounsaturated fatty acids for polyunsaturated fatty acids or a low-fat carbohydrate diet seem premature without more research into the effects on the development of atherosclerosis. Current opinions favoring monounsaturated fatty acids are based on epidemiological data and risk factor analysis, but are questioned by the demonstrated detrimental effects on atherosclerosis in animal models.