How relevant is the ratio of dietary n-6 to n-3 polyunsaturated fatty acids to cardiovascular disease risk? Evidence from the OPTILIP study

PURPOSE OF REVIEW: There has been much debate over the practical utility of the dietary ratio of n-6 to n-3 polyunsaturated fatty acids in optimizing the benefits of n-3 fatty acids (C18-C22) on cardiovascular health. This review examines the supporting evidence from the OPTILIP study within the context of the emerging consensus on the value of this dietary metric. RECENT FINDINGS: The question of whether the ratio of n-6/n-3 polyunsaturated fatty acids or total amounts of dietary polyunsaturated fatty acids is of more importance to cardiovascular health has been addressed recently in a randomly controlled trial (OPTILIP) and in a stable isotope tracer study. These two studies were independently unanimous in concluding that the ratio of n-6/n-3 polyunsaturated fatty acids is of no value in modifying cardiovascular disease risk. The latter study also showed that the absolute amounts of dietary linoleic acid and alpha-linolenic acid are of relevance to the efficiency of conversion of alpha-linolenic acid to eicosapentaenoic acid and docosahexaenoic acid. SUMMARY: This review should help to settle any outstanding controversy over the dietary ratio of n-6/n-3 polyunsaturated fatty acids. It reinforces current recommendations to increase the consumption of preformed eicosapentaenoic acid/docosahexaenoic acid in fish, and supports dietary measures to increase and decrease intakes alpha-linolenic acid and linoleic acid, respectively, to promote the endogenous synthesis of these longer chain n-3 polyunsaturated fatty acids.     

N-6 fatty acids and cardiovascular health: dietary intake recommendations

Omega-6 polyunsaturated fatty acids (n-6 PUFA) are well known for their critical role in many physiological functions and reduce risks of cardiovascular disease (CVD). However, some argue that excessive consumption of n-6 PUFA may lead to adverse effects on health and therefore recommend reducing dietary n-6 PUFA intake or fixing an upper limit. Epidemiological studies show that n-6 PUFA dietary intake significantly lowers blood LDL-cholesterol levels. In addition, n-6 PUFA intake lower several cardiovascular risk factors such as blood pressure, inflammatory markers, haemostatic parameters and obesity. Data from prospective cohort and interventional studies converge towards a specific protective role of dietary n-6 PUFA intake, in particular linoleic acid, against CVD. In regards to studies examined in this narrative review, recommendation for n-6 PUFA intake above 5%, and ideally about 10% of total energy appears justified for the prevention of ischemic heart disease.     

N-3 vs. saturated fatty acids: Effects on the arterial wall

Cardiovascular disease is a leading cause of death worldwide. Atherosclerosis and unstable plaques are underlying causes for cardiovascular diseases. Cardiovascular disease is associated with consumption of diets high in saturated fats. In contrast there is increasing evidence that higher intakes of dietary n-3 fatty acids decrease risk for cardiovascular disease. Recent studies are beginning to clarify how n-3 compared with saturated fatty acids influence cardiovascular disease risk via pathways in the arterial wall. In this paper we will review studies that report on mechanisms whereby dietary fatty acids affect atherosclerosis through modulation of arterial wall lipid deposition, inflammation, cell proliferation, and plaque vulnerability.     

Acculturation and Plasma Fatty Acid Concentrations in Hispanic and Chinese-American Adults: The Multi-Ethnic Study of Atherosclerosis

Background

Acculturation to the U.S. is associated with increased risk of cardiovascular disease, but the etiologic pathways are not fully understood. Plasma fatty acid levels exhibit ethnic differences and are emerging as biomarkers and predictors of cardiovascular disease risk. Thus, plasma fatty acids may represent one pathway underlying the association between acculturation and cardiovascular disease. We investigated the cross-sectional relationship between acculturation and plasma phospholipid fatty acids in a diverse sample of Hispanic- and Chinese-American adults.

Methods and Findings

Participants included 377 Mexican, 320 non-Mexican Hispanic, and 712 Chinese adults from the Multi-Ethnic Study of Atherosclerosis, who had full plasma phospholipid assays and acculturation information. Acculturation was determined from three proxy measures: nativity, language spoken at home, and years in the U.S., with possible scores ranging from 0 (least acculturated) to 5 (most acculturated) points. α-Linolenic acid, linoleic acid, eicosapentaenoic acid, docosahexaenoic acid, and arachidonic acid were measured in fasting plasma. Linear regression models were conducted in race/ethnicity-stratified analyses, with acculturation as the predictor and plasma phospholipid fatty acids as the outcome variables. We ran secondary analyses to examine associations between acculturation and dietary fatty acids for comparison. Covariates included age, gender, education, and income. Contrary to our hypothesis, no statistically significant associations were detected between acculturation and plasma phospholipid fatty acids for Chinese, non-Mexican Hispanic, or Mexican participants. However, acculturation was related to dietary total n-6 fatty acids and dietary n-3/n-6 ratios in expected directions for Mexican, non-Mexican Hispanic, and combined Hispanic participants. In Chinese individuals, acculturation was unexpectedly associated with lower arachidonic acid intake.

Conclusion

Absence of associations between acculturation and plasma phospholipid fatty acids suggests that changes in the plasma phospholipid fatty acids studied do not account for the observed associations of acculturation to the U.S. and cardiovascular disease risk. Similar findings were observed for eicosapentaenoic acid and docosahexaenoic acid, when using dietary intake. However, the observed associations between dietary n-6 fatty acids and acculturation in Hispanic individuals suggest that dietary intake may be more informative than phospholipids when investigating acculturation effects. In Chinese individuals, acculturation may have a possible protective effect through decreased arachidonic acid intake. Further research on dietary fatty acids and other cardiovascular disease biomarkers is needed to identify possible etiologic mechanisms between acculturation and cardiovascular disease.     

Dietary fat,fatty acid composition in plasma and the metabolic syndrome

PURPOSE OF REVIEW: The metabolic syndrome, a cluster of disorders often including abdominal obesity, is associated with a high risk of cardiovascular disease and premature death. Insulin resistance is a key feature of the metabolic syndrome. Observational studies have indicated that the type of fat in the diet may be related to the development of insulin resistance and the metabolic syndrome, also independent of possible effects on body weight. Dietary surveys are often imprecise. One way to monitor the type of fat in the diet is to record the fatty acid composition in plasma. This review summarizes recent data on the relationships between fatty acid composition in plasma and insulin resistance, diabetes and other disorders related to the metabolic syndrome. RECENT FINDINGS: Insulin resistance and insulin resistant states are often associated with the fatty acid pattern in plasma, characterized by an increased proportion of palmitic (16 : 0) and a low proportion of linoleic (18 : 2 n-6) acids, with a distribution of other fatty acids indicating an increased activity of delta-9 and delta-6 desaturase. This shows that there may be a causal relationship between the type of fat in the diet and insulin action, an assumption supported by recent dietary intervention studies. SUMMARY: In a public health perspective these results, from both observational and intervention studies, underline the importance of fat quality in the diet for the development of a number of prevalent diseases. Taken together with several earlier studies and recent epidemiological findings, they give strong support to present dietary guidelines.     

Dietary lipids and forages interactions on cow and goat milk fatty acid composition and sensory properties

This review summarises the known effects of dietary factors on bovine and caprine milk fatty acid composition, as well as the regulation of cow and goat mammary lipid secretion. Special attention is given to fatty acids that could play a role for human health, such as saturated fatty acids, oleic acid, n-6- or n-3-C18 to C22 polyunsaturated fatty acids, trans isomers of C18:1 and C18:2, and isomers of conjugated linoleic acid (CLA). The main dietary factors taken into account are the nature of forages, including pasture, the forage:concentrate ratio and diet starch content, and the supplementation of dairy rations with crude or processed vegetable oils or oilseeds, and vitamin E. A particular emphasis is given to studies on interactions between these dietary factors, which show that there is a considerable plasticity of ruminant milk fatty acid composition. Despite the existence of several studies on the effects of dietary factors on the sensorial quality of milk and dairy products, there is a need to evaluate more deeply how the different feeding strategies could change the nutritional, sensorial and technological aspects of milk fat quality.     

Trans fatty acids in hydrogenated fat inhibited the synthesis of the polyunsaturated fatty acids in the phospholipid of arterial cells

Our hypothesis that the trans fatty acids in hydrogenated fat inhibited the synthesis of polyunsaturated fatty acids in the phospholipid of arterial cells was tested with five groups each with six pregnant porcine fed from d 35 of gestation and during lactation. The basal diet contained 2% corn oil (control). The other four diets included the control + 10% butter or 10% hydrogenated fat plus two levels of Mg. Plasma, milk and aortic phospholipid fatty acids, phospholipid composition and calcium content of the aorta from the piglets were determined. At 48 +/- 2 d of age, the aorta phospholipid of piglets from porcine fed hydrogenated fat contained a significantly higher concentration of linoleic acid, less arachidonic acid, and less long chain polyunsaturated fatty acid (PUFA) than did piglets from porcine fed either butterfat or the control diet. Mg had no effect. These changes in composition in piglets from porcine fed hydrogenated fat indicate that trans fat inhibits the metabolic conversion of linoleic acid to arachidonic acid and to other n-6 PUFA. The aortic calcium content data showed a significant interaction of calcium concentration with age. We concluded: 1) that dietary trans fat perturbed essential fatty acid (EFA) metabolism which led to changes in the phospholipid fatty acid composition in the aorta, the target tissue of atherogenesis, 2) this inhibition of EFA to PUFA by the isomeric fatty acids in hydrogenated fat is a risk factor in the development of coronary heart disease.     

Cardiac proinflammatory pathways are altered with different dietary n-6 linoleic to n-3 alpha-linolenic acid ratios in normal, fat-fed pigs

Although dietary fat has been associated with inflammation and cardiovascular diseases (CVD), most studies have focused on individuals with preexisting diseases. However, the role of dietary fatty acids on inflammatory pathways before the onset of any abnormality may be more relevant for identifying initiating factors and interventions for CVD prevention. We fed young male pigs one of three diets differing in n-6 and n-3 polyunsaturated fatty acids (PUFA) linoleic acid (LA, 18:2n-6) and alpha-linolenic acid (ALA, 18:3n-3) for 30 days. Cardiac membrane phospholipid fatty acids, phospholipase A(2) (PLA(2)) isoform activities, and cyclooxygenase (COX)-1 and -2 and 5-lipoxygenase (5-LO) expression were measured. The low PUFA diet (% energy, 1.2% LA+0.06% ALA) increased arachidonic acid (AA) and decreased eicosapentaenoic acid (EPA) in heart membranes and increased Ca(2+)-independent iPLA(2) activity, COX-2 expression, and activation of 5-LO. Increasing dietary ALA while keeping LA constant (1.4% LA+1.2% ALA) decreased the heart membrane AA, increased EPA, and prevented proinflammatory enzyme activation. However, regardless of high ALA, high dietary LA (11.6% LA and 1.2% ALA) decreased EPA and led to a high heart membrane AA, and Ca(2+)-dependent cPLA(2) with a marked increase in nitrosative stress. Our results suggest that the potential cardiovascular benefit of ALA is achieved only when dietary LA is reduced concomitantly rather than fed with high LA diet. The increased nitrosative stress in the unstressed heart with high dietary LA suggests that biomarkers of nitrosative stress may offer a useful early marker of the effects of dietary fat on oxidative tissue stress.     

Antiarrhythmic effects of n-3 fatty acids: evidence from human studies

PURPOSE OF REVIEW: N-3 fatty acids from fish reduce cardiovascular mortality including sudden cardiac death. In this paper, the authors discuss the results of human studies with regard to the hypothesis that n-3 fatty acids reduce the risk of fatal coronary heart disease through antiarrhythmic effects. RECENT FINDINGS: Results from two recent clinical trials do not support a protective effect of n-3 fatty acids. In light of the earlier published bulk of evidence that n-3 fatty acids reduce cardiovascular mortality and sudden cardiac death, it is hard to explain these findings. Two recent observational studies confirmed that intake of n-3 fatty acids from fish is associated with less cardiovascular disease in the general population. They indicated that the protective effect of a fish meal may depend on the n-3 fatty acid content or preparation method and suggested a protective effect on arrhythmia rather than on atherosclerosis. Intervention studies on electrophysiological predictors of arrhythmia do not clearly confirm a beneficial effect of n-3 fatty acids. However, most of these studies were small or performed in healthy populations. SUMMARY: The available evidence still suggests that n-3 fatty acids may prevent fatal cardiac arrhythmia, but more conclusive studies are urgently needed.     

Thematic review series: patient-oriented research. Dietary fat, carbohydrate, and protein: effects on plasma lipoprotein patterns

In general, under isoweight conditions, different types of dietary protein or individual amino acids have little effect on lipoprotein patterns. Dietary carbohydrate tends to increase plasma triglyceride when it displaces fat, accompanied by a decrease in HDL cholesterol concentrations. Potential differential effects of types of carbohydrate are difficult to assess because of differences in rates of absorption and confounding of dietary fiber. Saturated fatty acids increase LDL and HDL cholesterol, whereas trans fatty acids increase LDL but not HDL cholesterol. Unsaturated fatty acids decrease LDL and HDL cholesterol, polyunsaturated more so than monounsaturated. There has been considerable interest in the potential benefit of major shifts in dietary macronutrients on weight loss and lipoprotein patterns. Short-term data favor substituting protein and fat for carbohydrate, whereas long-term data have failed to show a benefit for weight loss. During an active weight loss period low-carbohydrate diets more favorably affect triglyceride and HDL and less favorably affect LDL cholesterol concentrations. Additional efforts need to be focused on gaining a better understanding of the effect of dietary macronutrient profiles on established and emerging cardiovascular disease risk factors, mechanisms for changes observed and contributors to individual variability. Such data are needed to allow reassessment and, if necessary, modification of current recommendations.     

Long chain omega-3 fatty acids: Micronutrients in disguise

Considerable information has accumulated to show that DHA and EPA have unique roles that differ from other n-3 fatty acids and the n-6 fatty acids, with increasing understanding of the mechanisms through which these fatty acids reduce risk of disease. DHA and EPA regulate hepatic lipid and glucose metabolism, but are present in foods of animal origin, which are generally high in protein with variable triglycerides and low carbohydrate. Biological activity at intakes too low to provide significant amounts of energy is consistent with the definition of a vitamin for which needs are modified by life-stage, diet and genetic variables, and disease. Recent studies reveal that DHA may play a central role in co-coordinating complex networks that integrate hepatic glucose, fatty acid and amino acid metabolism for the purpose of efficient utilization of dietary protein, particularly during early development when the milk diet provides large amounts of energy from fat.     

Effect of replacing calcium salts of palm oil distillate with extruded linseeds on milk fatty acid composition in Jersey and Holstein cows

Clinical and biomedical studies have provided evidence for the critical role of n-3 fatty acids on the reduction of chronic disease risk in humans, including cardiovascular disease. In the current experiment, the potential to enhance milk n-3 content in two breeds with inherent genetic differences in mammary lipogenesis and de novo fatty acid synthesis was examined using extruded linseeds. Six lactating cows (three Holstein and three Jersey) were used in a two-treatment switchback design with 3 × 21-day experimental periods to evaluate the effect of iso-energetic replacement of calcium salts of palm oil distillate (CPO) in the diet (34 g/kg dry matter (DM)) with 100 g/kg DM extruded linseeds (LIN). For both breeds, replacing CPO with LIN had no effect (P > 0.05) on DM intake or milk yield, but reduced (P < 0.05) milk fat and protein yield (on average, from 760 to 706 and 573 to 552 g/day, respectively). Relative to CPO, the LIN treatment reduced (P < 0.01) total saturated fatty acid content and enhanced (P < 0.001) 18:3n-3 in milk, whereas breed by diet interactions were significant for milk fat 16:0, total trans fatty acid and conjugated linoleic acid concentrations. Increases in 18:3n-3 intake derived from LIN in the diet were transferred into milk with a mean marginal transfer efficiency of 1.8%. Proportionate changes in milk fatty acid composition were greater in the Jersey, highlighting the importance of diet-genotype interactions on mammary lipogenesis. More extensive studies are required to determine the role of genotype on milk fat composition responses to oilseeds in the diet.     

Influence of dietary partially hydrogenated fat high in trans fatty acids on lipid composition and function of intestinal brush border membrane in rats

The effect of dietary hydrogenated fat (Indian vanaspati) high in trans fatty acids (6 en%) on lipid composition, fluidity and function of rat intestinal brush border membrane was studied at 2 and 8 en% of linoleic acid. Three groups of weanling rats were fed rice-pulse based diet containing 10% fat over a ten week period: Group I (groundnut oil), Group II (vanaspati), Group III (vanaspati + safflower oil). The functionality of the brush border membrane was assessed by the activity of membrane bound enzymes and transport of D-glucose and L-leucine. The levels of total cholesterol and phospholipids were similar in all groups. The data on fatty acid composition of membrane phospholipids showed that, at 2 en% of linoleic acid in the diet, trans fatty acids lowered arachidonic acid and increased linoleic acid contents indicating altered polyunsaturated fatty acid metabolism. Alkaline phosphatase activity was increased while the activities of sucrase, gamma-glutamyl transpeptidase and transport of D-glucose and L-leucine were not altered by dietary trans fatty acids. However at higher intake of linoleic acid in the diet, trans fatty acids have no effect on polyunsaturated fatty acid composition and alkaline phosphatase activity of intestinal brush border membrane. These data suggest that feeding dietary fat high in trans fatty acids is associated with alteration in intestinal brush border membrane polyunsaturated fatty acid composition and alkaline phosphatase activity only when the dietary linoleic acid is low.     

Dietary n-3 fats as adjunctive therapy in a prototypic inflammatory disease: issues and obstacles for use in rheumatoid arthritis

Eicosanoids derived from the n-6 fatty acid, arachidonic acid, and the cytokines interleukin-1beta and tumour necrosis factor-alpha are involved in the signs and symptoms of inflammatory joint disease, as well as the cartilage degradation seen in established rheumatoid arthritis (RA). Then n-3 fatty acids in fish and fish oil can inhibit production of both eicosanoid and cytokine inflammatory mediators and therefore, have the potential to modify RA pathology. Epidemiological studies suggest that fish intake may be preventive for RA and double-blind placebo-controlled studies demonstrate that dietary fish oil can alleviate the signs and symptoms of RA. The implementation of these findings will require among other things, a range of n-3 fat enriched foods, as well as physician awareness of the possibilities for dietary n-3 fat increases to be used as adjunctive therapy in RA.     

Impact of maternal dietary n-3 and n-6 fatty acids on milk medium-chain fatty acids and the implications for neonatal liver metabolism

Levels of n-6, n-3, and medium-chain fatty acids (MCFA) in milk are highly variable. Higher carbohydrate intakes are associated with increased mammary gland MCFA synthesis, but the role of unsaturated fatty acids for milk MCFA secretion is unclear. This study addressed whether n-6 and n-3 fatty acids, which are known to inhibit hepatic fatty acid synthesis, influence MCFA in rat and human milk and the implications of varying MCFA, n-6, and n-3 fatty acids in rat milk for metabolic regulation in the neonatal liver. Rats were fed a low-fat diet or one of six higher-fat diets, varying in 16:0, 18:1n-9, 18:2n-6, 18:3n-3, and long-chain (LC) n-3 fatty acids. Higher maternal dietary 18:2n-6 or 18:3n-3 did not influence milk MCFA, but lower maternal plasma triglycerides, due to either a low-fat or a high-fat high-LC n-3 diet led to higher milk MCFA. MCFA levels were inversely associated with 18:1n-9, 18:2n-6, and 18:3n-3 in human milk, likely reflecting the association between dietary total fat and unsaturated fatty acids. High LC n-3 fatty acid in rat milk was associated with lower hepatic Pklr, Acly, Fasn, and Scd1 and higher Hmgcs2 in the milk-fed rat neonate, with no effect of milk 18:1n-9, 18:2n-6, or MCFA. These studies show that the dietary fatty acid composition does not impact MCFA secretion in milk, but the fatty acid composition of milk, particularly the LC n-3 fatty acid, is relevant to hepatic metabolic regulation in the milk-fed neonate.     

Could the Quality of Dietary Fat,and Not Just Its Quantity,Be Related to Risk of Obesity?

This review focuses on the possible association between types of fatty acids and weight change. It examines the biological plausibility underlining these associations and the evidence obtained to date from clinical trials and epidemiological studies. Animal studies have shown that dietary short- and medium-chain fatty acids compared to long-chain fatty acids appear to promote weight loss. Similarly, monounsaturated fatty acids (MUFAs) appear to favor weight loss compared to saturated fatty acids (SFAs) in human studies. The structure of fatty acids seems to affect their degree of oxidation and deposition. Although results are conflicting, human studies follow the general trend reported in animal studies. These trials suggest that some fatty acids are prone to oxidation and some others lead to fat storage when comparing isocaloric diets. For instance, n-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic and docosahexaenoic acids are preferentially oxidizied to other PUFA but results remain inconsistent. Epidemiological studies concerning this issue reported that total dietary fat, which includes MUFA, PUFA, and SFA could increase the risk of obesity, but results are few and conflicting. The rising biological plausibility linking dietary fat quality and risk of obesity, together with the rather recent addition of fatty acids content in food composition tables, support the need for major epidemiological studies in that area.     

The role of n-3 fatty acids in gestation and parturition

Preterm birth is the most common cause of low infant birth weight and infant morbidity and mortality. Evidence from human and animal studies indicates that essential fatty acids of both the n-3 and n-6 series, and their eicosanoid metabolites, play important and modifiable roles in gestational duration and parturition, and n-3 fatty acid intake during pregnancy may be inadequate. Prostaglandins (PG) of the 2-series are involved in parturition and connective tissue remodeling associated with cervical maturation and rupture of membranes. In the absence of infections, preterm birth is characterized by lower reproductive tissue PG production and decreased inducible cyclooxygenase expression. Women who deliver prematurely have increased pools of n-6 fatty acid and decreased n-3 fatty acids, despite the lower PG production. Several human pregnancy supplementation trials with n-3 fatty acids have shown a significant reduction in the incidence of premature deliver and increased birth weight associated with increased gestational duration. Supplementation with long chain n-3 fatty acids such as docosahexaenoic acid may be useful in prolonging the duration of gestation in some high-risk pregnancies. Evidence presented in this review is discussed in terms of the roles of dietary n-3 and n-6 fatty acids in gestation and parturition, mechanisms by which they may influence gestational duration and the human trials suggesting that increased dietary long-chain n-3 fatty acids decrease the incidence of premature delivery.     

The metabolism of (n-3) and (n-6) fatty acids and their oxygenation by platelet cyclooxygenase and lipoxygenase

Arachidonic acid is the principal unsaturated acid in most membrane lipids. Membrane lipids also contain a variety of other (n-6) and (n-3) fatty acids. The amounts of (n-6) and (n-3) fatty acids in membrane lipids can be modified by dietary fat change. Our studies show that long chain (n-6) and (n-3) acids are metabolized by platelet lipoxygenase and cyclooxygenase. When cells are exposed to various agonists, a variety of unsaturated fatty acids may be released. Our studies show that they have the potential of modifying physiological function both by mediating arachidonic acid metabolism and as direct precursors for oxygenated metabolites which themselves may interact with specific receptors to regulate biological processes.     

The effect of dietary fish oils on eicosanoid biosynthesis in peritoneal macrophages is influenced by both dietary N-6 polyunsaturated fats and total dietary fat

Recent research has implicated dietary fish oils in the reduction of eicosanoids formed from arachidonic acid and amelioration of chronic diseases such as coronary heart disease, atherosclerosis and inflammation. Feeding studies were conducted to determine if the efficacy of dietary n-3 polyunsaturated fatty acids (PUFA) from fish oils was influenced by the quantity of n-6 polyunsaturated fatty acids and the total level of fat in the diet. Groups of mice were fed diets composed of 5 and 20% total fat with varying proportions of linoleic acid as a source of n-6 PUFA. Menhaden oil as a source of n-3 PUFA was fed at two levels of n-6 at each level of total fat. Eicosanoid biosynthesis was stimulated and assayed in the mouse peritoneum using zymosan as an inflammatory stimulus. Production of LTE4 and PGE2 was enhanced by increasing n-6 PUFA in the diet at both levels of total fat. High dietary fat significantly suppressed leukotriene (LT) synthesis. Dietary menhaden oil reduced LTE4 and PGE2 synthesis at both levels of dietary n-6 in the low fat study. In animals on 20% dietary fat menhaden oil significantly reduced LT synthesis only at a relatively low dietary n-6 PUFA. On a high n-6 PUFA high fat diets, menhaden oil did not significant affect LTE4 synthesis in response to zymosan stimulation. The results suggest that the effectiveness of fish oils in reducing eicosanoids in response to specific stimulation is influenced by the level of n-6 and the total quantity of fat in the diet.