Lipid nutrition: "In silico" studies and undeveloped experiments.

This review examines lipids and lipid-binding sites on proteins in relation to cardiovascular disease. Lipid nutrition involves food energy from ingested fatty acids plus fatty acids formed from excess ingested carbohydrate and protein. Non-esterified fatty acids (NEFA) and lipoproteins have many detailed attributes not evident in their names. Recognizing attributes of lipid-protein interactions decreases unexpected outcomes. Details of double bond position and configuration interacting with protein binding sites have unexpected consequences in acyltransferase and cell replication events. Highly unsaturated fatty acids (HUFA) have n-3 and n-6 motifs with documented differences in intensity of destabilizing positive feedback loops amplifying pathophysiology. However, actions of NEFA have been neglected relative to cholesterol, which is co-produced from excess food. Native low-density lipoproteins (LDL) bind to a high-affinity cell surface receptor which poorly recognizes biologically modified LDLs. NEFA increase negative charge of LDL and decrease its processing by "normal" receptors while increasing processing by "scavenger" receptors. A positive feedback loop in the recruitment of monocytes and macrophages amplifies chronic inflammatory pathophysiology. Computer tools combine multiple components in lipid nutrition and predict balance of energy and n-3:n-6 HUFA. The tools help design and execute precise clinical nutrition monitoring that either supports or disproves expectations.

An abundance of seafood consumption studies presents new opportunities to evaluate effects on neurocognitive development.

The relationship between seafood eaten during pregnancy and neurocognition in offspring has been the subject of considerable scientific study for over 25 years. Evaluation of this question led two scientific advisory committees to the Dietary Guidelines for Americans (DGAC), the Food and Agriculture Organization of the United Nations with the World Health Organization (FAO/WHO), Health Canada, the European Food Safety Authority (EFSA), and the U.S. Food and Drug Administration (FDA) to conclude through 2014 that seafood consumed by pregnant women is likely to benefit the neurocognitive development of their children. The evidence they reviewed included between four and ten studies of seafood consumption during pregnancy that reported beneficial associations. In contrast there are now 29 seafood consumption studies available describing over 100,000 mothers-child pairs and 15 studies describing over 25,000 children who ate seafood. A systematic review of these studies using Nutrition Evaluation Systematic Review methodology is warranted to determine whether recent research corroborates, builds on, or significantly alters the previous conclusions. Studies that evaluate the integrated effects of seafood as a complete food more directly and completely evaluate impacts on neurocognition as compared to studies that evaluate individual nutritients or toxicological constituents in isolation. Here we address how the findings could add to our understanding of whether seafood consumed during pregnancy and early childhood affects neurocognition, including whether such effects are clinically meaningful, lasting, related to amounts consumed, and affected by any neurotoxicants that may be present, particularly mercury, which is present at varying levels in essentially all seafood. We provide the history, context and rationale for reexamining these questions in light of currently available data.

Relationships between seafood consumption during pregnancy and childhood and neurocognitive development: Two systematic reviews.

Abundant data are now available to evaluate relationships between seafood consumption in pregnancy and childhood and neurocognitive development. We conducted two systematic reviews utilizing methodologies detailed by the Dietary Guidelines for Americans Scientific Advisory Committee 2020-2025. After reviewing 44 publications on 106,237 mother-offspring pairs and 25,960 children, our technical expert committee developed two conclusion statements that included the following: "Moderate and consistent evidence indicates that consumption of a wide range of amounts and types of commercially available seafood during pregnancy is associated with improved neurocognitive development of offspring as compared to eating no seafood. Overall, benefits to neurocognitive development began at the lowest amounts of seafood consumed (∼4 oz/wk) and continued through the highest amounts, above 12 oz/wk, some range up to >100 oz/wk.", "This evidence does not meet the criteria for "strong evidence" only due to a paucity of randomized controlled trials that may not be ethical or feasible to conduct for pregnancy" and "Moderate and consistent evidence indicates that consumption of >4 oz/wk and likely >12 oz/wk of seafood during childhood has beneficial associations with neurocognitive outcomes." No net adverse neurocognitive outcomes were reported among offspring at the highest ranges of seafood intakes despite associated increases in mercury exposures. Data are insufficient for conclusive statements regarding lactation, optimal amounts, categories or specific species characterized by mercury content and neurocognitive development; although there is some evidence that dark/oily seafood may be more beneficial. Research was conducted in healthy women and children and is generalizable to US populations. Assessment of seafood as a whole food integrates inherently integrates any adverse effects from neurotoxicants, if any, and benefits to neurocognition from omega-3 fats, as well as other nutrients critical to optimal neurological development. Understanding of the effects of seafood consumption on neurocognition can have significant public health implications.

Validation of an equation predicting highly unsaturated fatty acid (HUFA) compositions of human blood fractions from dietary intakes of both HUFAs and their precursors.

Proportions of omega-3 (n-3) and omega-6 (n-6) in 20- and 22-carbon highly unsaturated fatty acids with 3 or more double bonds (HUFA) accumulated in tissue HUFA (e.g., the %n-6 in HUFA) are biomarkers reflecting intakes of n-6 and n-3 fatty acids. An empirical equation, referred to here as the Lands' Equation, was developed previously to use dietary intakes of n-6 and n-3 HUFA and their 18-carbon precursors to estimate the %n-6 in HUFA of humans. From the PubMed database, we identified clinical trials reporting (a) dietary intake of at least linoleic acid (18:2n-6) and alpha-linolenic acid (18:3n-3), and (b) the amounts of at least arachidonic acid (20:4n-6), eicosapentaenoic acid (20:5n-3), and docosahexaenoic acid (22:6n-3) in lipids of plasma, serum, or red blood cell. Linear regression analyses comparing reported and predicted %n-6 in HUFA gave a correlation coefficient of 0.73 (p<0.000000) for 34 studies with 92 subject groups. These results indicate that circulating HUFA compositions can be reliably estimated from dietary intake data that not only includes n-3 and n-6 HUFA consumption, but also includes consumption of 18 carbon n-3 and n-6 precursor fatty acids.

Highly unsaturated fatty acids (HUFA) mediate and monitor food's impact on health.

A hyperbolic, saturable, competitive dynamic of ligand binding to metabolic enzymes and lipid mediator receptors gives non-linear dose-response interactions that need careful management when planning or interpreting nutrient-based interventions. Relatively indiscriminate metabolism during accumulation of HUFA from n-3 and n-6 nutrients allows the amounts of n-3 and n-6 nutrients to determine the HUFA balance accumulated in tissue phospholipids. However, when HUFA-based eicosanoid actions are more intense with n-6 than n-3 mediators, they cause healthy physiology to shift toward pathophysiology. The proportion of n-6 in tissue HUFA directly relates to the severity of conditions caused by excessive n-6 actions. In the absence of n-3 nutrients, dietary linoleate (18:2n-6) has a very narrow therapeutic window below 1 percent of food energy, and it is widened by n-3 nutrients. The predictable quantitative dynamics of competing n-3 and n-6 nutrients allows design of successful preventive nutrition protocols that confirm and extend the epidemiologically observed benefits of n-3 nutrients.

Benefit-Risk Assessment of Fish Oil in Preventing Cardiovascular Disease.

Cardiovascular disease (CVD) is a preventable disease, which combines two general processes: chronic vascular inflammation and acute thrombosis. Both are amplified with positive feedback signals by n-6 eicosanoids derived from food-based n-6 highly unsaturated fatty acids (n-6 HUFA). This amplification is lessened by competing actions of n-3 HUFA. Death results from fatal interactions of the vascular wall with platelets and clotting proteins. The benefits of fish oil interventions are confounded by complex details in pharmacokinetics, pharmacodynamics, adverse events, timescale factors, topology, financial incentives and people's sense of cause and effect. Two basic aspects of n-3 HUFA that are overlooked in CVD dynamics are saturable, hyperbolic responses of the enzymes continually supplying n-6 HUFA and hard-to-control positive feedback receptor signals by excessive n-6 HUFA-based mediators. Multiple feedback loops in inflammation and thrombosis have diverse mediators, and reducing one mediator that occurs above its rate-limiting levels may not reduce the pathophysiology. Clinicians have developed some successful interventions that decrease CVD deaths in the form of secondary prevention. However, the current high CVD prevalence in the USA remains unchanged, and successful primary prevention of CVD remains uncertain. This review weighs the available evidence to help clinicians, the biomedical community and the public put the use of fish oil supplements into a balanced perspective.

Omega-3 PUFAs Lower the Propensity for Arachidonic Acid Cascade Overreactions.

A productive view of the benefits from omega-3 (n-3) nutrients is that the dietary essential omega-6 (n-6) linoleic acid has a very narrow therapeutic window which is widened by n-3 nutrients. The benefit from moderate physiological actions of the arachidonic acid cascade can easily shift to harm from excessive pathophysiological actions. Recognizing the factors that predispose the cascade to an unwanted overactivity gives a rational approach for arranging beneficial interactions between the n-3 and n-6 essential nutrients that are initial components of the cascade. Much detailed evidence for harmful cascade actions was collected by pharmaceutical companies as they developed drugs to decrease those actions. A remaining challenge is to understand the factors that predispose the cascade toward unwanted outcomes and create the need for therapeutic interventions. Such understanding involves recognizing the similar dynamics for dietary n-3 and n-6 nutrients in forming the immediate precursors of the cascade plus the more vigorous actions of the n-6 precursor, arachidonic acid, in forming potent mediators that amplify unwanted cascade outcomes. Tools have been developed to aid deliberate day-to-day quantitative management of the propensity for cascade overactivity in ways that can decrease the need for drug treatments.

Balancing proportions of competing omega-3 and omega-6 highly unsaturated fatty acids (HUFA) in tissue lipids.

People eating different balances of omega-3 and omega-6 nutrients develop predictably different proportions of competing highly unsaturated fatty acids (HUFA) in their tissue lipids. While epidemiological studies have associated wide differences in HUFA balance with disease severity, some clinical studies that did not examine wide differences failed to confirm the association. We examined the degree to which the relative amount of arachidonic acid, the major precursor of omega-6 eicosanoids, differs among people who have widely different dietary intakes of omega-3 and omega-6 nutrients. Gas chromatographic analyses of human blood samples describe the balance among n-3 and n-6 HUFA for different individuals. The proportion of the omega-6 arachidonic acid, from which potent eicosanoids are formed, is not constant. It ranges from 30% to 70% of HUFA while the competing n-3 HUFA range from 60% to 10% of HUFA. Significant differences in clinical outcomes between control and intervention groups have been seen when using dietary interventions that shift the balance of n-3 and n-6 nutrients far enough to create a biologically significant difference in the HUFA balance.

Dietary omega-3 and omega-6 fatty acids compete in producing tissue compositions and tissue responses.

Serious food-related health disorders may be prevented by recognizing the molecular processes that connect the dietary intake of vitamin-like fatty acids to tissue accumulation of precursors of potent hormone-like compounds that cause harmful tissue responses. Conversion of dietary 18-carbon omega-3 and omega-6 polyunsaturated fatty acids to tissue 20- and 22-carbon highly unsaturated fatty acids (HUFAs) is catalyzed by promiscuous enzymes that allow different types of fatty acid to compete among each other for accumulation in tissue HUFA. As a result, food choices strongly influence the types of accumulated tissue HUFA. However, the conversion of tissue HUFA to active hormones and their receptor-mediated actions occurs with discriminating enzymes and receptors that give more intense responses for the omega-6 and omega-3 hormones. Undesired chronic health disorders, which are made worse by excessive omega-6 hormone actions, can be prevented by eating more omega-3 fats, less omega-6 fats, and fewer calories per meal.

Historical perspectives on the impact of n-3 and n-6 nutrients on health.

Current public advice from the Food and Nutrition Board (FNB) about essential fatty acids (EFA) has limited quantitative details about three processes: (1) similar dynamics for n-3 linolenic and n-6 linoleic polyunsaturated fatty acids (PUFA) in maintaining 20- and 22-carbon n-3 and n-6 highly unsaturated fatty acids (HUFA) in tissues; (2) different dynamics for tissue n-3 and n-6 HUFA during formation and action of hormone-like eicosanoids; (3) simultaneous formation of non-esterified fatty acids (NEFA) and low density lipoprotein (LDL) from very low density lipoprotein (VLDL) formed from excess food energy and secreted by the liver. This report reviews evidence that public health may benefit from advice to eat less n-6 nutrients, more n-3 nutrients and fewer calories per meal. Explicit data for linoleic acid fit an Estimated Average Requirement (EAR) near 0.1 percent of daily food energy (en%) meeting needs of half the individuals in a group, a Recommended Dietary Allowance (RDA) near 0.5 en% meeting needs of 97-98 percent of individuals, and a Tolerable Upper Intake Level (UL) near 2 en% having no likely risk of adverse health effects. Quantitative tools help design and monitor explicit interventions that could beneficially replace imprecise advice on "healthy foods" with explicit preventive nutrition.

Consequences of essential fatty acids.

Essential fatty acids (EFA) are nutrients that form an amazingly large array of bioactive mediators that act on a large family of selective receptors. Nearly every cell and tissue in the human body expresses at least one of these receptors, allowing EFA-based signaling to influence nearly every aspect of human physiology. In this way, the health consequences of specific gene-environment interactions with these nutrients are more extensive than often recognized. The metabolic transformations have similar competitive dynamics for the n-3 and n-6 homologs when converting dietary EFA from the external environment of foods into the highly unsaturated fatty acid (HUFA) esters that accumulate in the internal environment of cells and tissues. In contrast, the formation and action of bioactive mediators during tissue responses to stimuli tend to selectively create more intense consequences for n-6 than n-3 homologs. Both n-3 and n-6 nutrients have beneficial actions, but many common health disorders are undesired consequences of excessive actions of tissue n-6 HUFA which are preventable. This review considers the possibility of preventing imbalances in dietary n-3 and n-6 nutrients with informed voluntary food choices. That action may prevent the unintended consequences that come from eating imbalanced diets which support excessive chronic actions of n-6 mediators that harm human health. The consequences from preventing n-3 and n-6 nutrient imbalances on a nationwide scale may be very large, and they need careful evaluation and implementation to avoid further harmful consequences for the national economy.

Using 3-6 differences in essential fatty acids rather than 3/6 ratios gives useful food balance scores.

BACKGROUND: The vitamin-like omega-3 and omega-6 essential fatty acids are converted in the body to a large family of hormones which act at selective receptors that occur on nearly every cell and tissue. A relative omega-3 deficit allows overabundant actions of omega-6 hormones to develop into health disorders. People need simple, explicit information on the balance of essential fatty acids in their foods to avoid accumulating unintended imbalances in their tissue omega-3 and omega-6 fatty acids. RESULTS: We developed an Omega 3-6 Balance Food Score that summarizes in a single value the balance among eleven omega-3 and omega-6 essential fatty acids in a food. The value allows a quantitative estimate of the impact of each food item on the proportions of omega-3 and omega-6 that will accumulate in the 20- and 22-carbon highly unsaturated fatty acids of blood, which is an important health risk assessment biomarker. CONCLUSIONS: The impact of an individual food item upon a useful health risk assessment biomarker is easily evident in a simple, explicit value for the balance among eleven essential fatty acids nutrients. Foods with more positive Omega 3-6 Balance Food Scores will increase the percent of omega-3 in the biomarker, whereas those with more negative Scores will increase the percent of omega-6 in the biomarker.

Prevent the cause, not just the symptoms.

If people stay healthy, less health care treatments need to be paid. Alternatively, health care treatments are uneconomical and unethical when they only remove signs and symptoms and leave the primary cause neglected and unchanged to cause future harm. Neglected preventable causes continue to cause massive health-related financial loss in the US. Monitoring imbalances of omega-3 and omega-6 hormone precursors in individuals can increase awareness and motivation for making efforts to prevent this pervasive diet-related cause of dysfunction, disease and financial loss. We now have low-cost tools for individuals to monitor their balance of omega-3 and omega-6 hormone precursors and to identify and choose foods that will maintain a desired balance and a desired quality of life.

Using a fingertip whole blood sample for rapid fatty acid measurement: method validation and correlation with erythrocyte polar lipid compositions in UK subjects.

It is well accepted that n-3 long-chain PUFA intake is positively associated with a range of health benefits. However, while benefits have been clearly shown, especially for CVD, the mechanisms for prevention/benefit are less understood. Analysis of plasma and erythrocyte phospholipids (PL) have been used to measure the status of the highly unsaturated fatty acids (HUFA), especially EPA (20 : 5n-3) and DHA (22 : 6n-3), although the time and complexity of the process places limitations on the sample numbers analysed. An assay has been developed using whole blood, collected by finger prick, and stored on absorbant paper, subjected to direct methylation and fatty acids quantified by automated GC. Tests on fatty acid stability show that blood samples are stable when stored at - 20°C for 1 month although some loss of HUFA was seen at 4°C. A total of fifty-one patients, including twenty-seven who consumed no fatty acid supplements, provided a blood sample for analysis. Concentrations of all major fatty acids were measured in erythrocyte PL and whole blood. The major HUFA, including EPA, DHA and arachidonic acid (ARA; 20 : 4n-6), as well as the ARA:EPA ratio and the percentage n-3 HUFA/total HUFA all showed good correlations, between erythrocyte PL and whole blood. Values of r2 ranged from 0.48 for ARA to 0.95 for the percentage of n-3 HUFA/total HUFA. This assay provides a non-invasive, rapid and reliable method of HUFA quantification with the percentage of n-3 HUFA value providing a potential blood biomarker for large-scale nutritional trials.

Dietary ω3 fatty acids modulate the substrate for post-operative atrial fibrillation in a canine cardiac surgery model.

AIMS: Pre-treatment with dietary ω3 polyunsaturated fatty acids (ω3-PUFA) has been reported to reduce the incidence of new-onset atrial fibrillation (AF) following cardiac surgery. In a canine cardiac surgery model, we evaluated the impact of dietary ω3-PUFA on atrial electrophysiological properties, inflammatory markers, the atrial endothelin-1 (ET-1) system, and the expression and distribution of connexin 43. METHODS AND RESULTS: Adult mongrel dogs received either normal chow (NC, n = 11) or chow supplemented with fish oil (FO, 0.6 g ω3-PUFA/kg/day, n = 9) for 3 weeks before surgery. A left thoracotomy was performed, and the left atrial appendage (LAA) was excised. Atrial pacing/recording wires were placed, and the pericardium/chest was closed. The atrial ratio of ω6/ω3 lipids decreased from 15-20 in NC to 2-3 in FO. FO treatment lowered pre-surgical and stabilized post-surgical arachidonate levels. Peak neutrophil to lymphocyte ratio was lower and decayed faster in FO-treated animals. Extensive inflammatory cell infiltration was present in NC atria, but was reduced in FO-treated dogs. FO-treated animals had lower post-surgical atrial expression of inducible nitric oxide synthase (iNOS) and reduced plasma ET-1. Expression of ET-1 and inositol trisphosphate receptor type-2 proteins in the LAA was also reduced. FO treatment prolonged post-operative atrial effective refractory period, slowed heart rate, and enhanced heart rate variability. Importantly, AF (>30 s) was inducible in four of six NC dogs, but no FO dogs. CONCLUSION: Dietary FO attenuated AF inducibility following cardiac surgery by modulating autonomic tone and heart rate. FO also reduced atrial inflammation, iNOS, and ET-1 expression.

False profits and silent partners in health care.

Traditional health care services have focused more on treatment of signs and symptoms of cardiovascular disease rather than on prevention of primary causal factors. This bias created a nation with increasing numbers of older people paying for increasing treatment costs. Treatment-oriented clinicians, drug companies and hospitals take a major proportion of ever-increasing health care dollars. Without prevention, American families gain little long-term relief from the highest health care treatment costs in the world. A lack of public accountability for valid surrogate endpoints continues to drain funds for treatments that do not remove underlying primary causes. It seems unethical and uneconomical to withhold community-wide primary prevention advice and only attend to people with clinical signs of disease. Also, treatments that remove a sign or symptom without removing the primary cause unethically set a sense of improved health while leaving unchanged the cause to continue harming future generations. A good alternative would be long-term primary prevention that removes primary causal factors and prevents the onset of signs and symptoms of disease. Health insurance companies could be effective partners with corporate and individual subscribers by diverting resources toward preventing proved primary causes of disease. A chain of molecular events that causally connects modifiable food choices to many health disorders has a measurable mediator: the proportions of omega-3 and omega-6 in tissue highly unsaturated fatty acids (HUFA). Health risk assessment can monitor the diet-based proportions of tissue HUFA which influence hundreds of vital physiologic events. Many financial losses will likely be decreased by primary prevention advice to choose foods that increase intakes of omega-3 fats, decrease intakes of omega-6 fats and include fewer calories per meal.

Planning primary prevention of coronary disease.

Effective prevention of the current annual $400 billion losses from atherosclerosis and cardiovascular disease (CVD) will require preventing primary causes rather than just decreasing signs and symptoms (risk factors) produced by those causes. All CVD risk factors predict a likelihood of CVD, but not all are causes of CVD. As a result, reducing some health risk assessment biomarkers may not appreciably reduce CVD and death. Careful review of molecular events connecting diets to death identifies two modifiable food imbalances that cause major chronic diseases in Americans. They are 1) imbalance between ingestion and expenditure of food energy, and 2) imbalance between omega-3 and omega-6 essential fatty acid levels in ingested foods. Health insurers could reduce costs and revolutionize preventive health care by monitoring omega-3 and omega-6 proportions in blood fatty acids and by using personalized interactive food choice software to adjust food intakes to fit individual preferences.

A critique of paradoxes in current advice on dietary lipids.

Beliefs about credible hypotheses of dietary causes of disease still need well-defined mediators to test for logical proof or disproof. We know that food energy causes transient postprandial oxidative insults that may not be fully reversible. Also, eating vitamin-like 18-carbon polyunsaturated fatty acids (PUFA) in foods maintains the 20- and 22-carbon highly unsaturated fatty acids (HUFA) in tissues. Tissue HUFA form hormone-like mediators that each amplify transient postprandial insults into fatal inflammatory, thrombotic and arrhythmic events in cardiovascular disease, a major preventable cause of death. Similar diet-based amplified events may also occur in other inflammatory proliferative disorders including cancer, dementia, arthritis and asthma. Puzzling paradoxes come from fragmented views of this situation which convey incomplete knowledge in oversimplified messages. Tools now exist to demonstrate successful prevention of two fatal food imbalances with credible dietary preventive interventions, but organizers and financers to help gather the evidence remain unknown. The overall evidence accumulated about diet, disease and death may be nearing a paradigm shift in which prior observed facts remain while beliefs about their accepted interpretation change.