HUFA Balance in Designing Successful Preventioneicosanoid Nix6 Eat3
HUFA balance is an important intermediate in the etiology of food-related health conditions. HUFA balance controls the relative amounts of n-3 and n-6 eicosanoids, and n-6 over-reactions shift healthy physiology toward inflammatory pathophysiology. (1.3 Prevention requires altering “upstream” events whereas treatment often attends to “downstream” events.[click Figure for details.]


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. Predictable quantitative dynamics of competing n-3 and n-6 nutrients allow design of successful preventive protocols that confirm and extend observed epidemiologically benefits of eating n-3 nutrients. Lands B. Highly  unsaturated fatty acids (HUFA) mediate and monitor food’s impact on health. Prostaglandins Other Lipid Mediat. 2017 May 20. pii: S1098-8823(17)30003-5. doi:  10.1016/j.prostaglandins.2017.05.002.  PMID: 28535956

Cardiovascular disease (CVD) is a preventable disease which combines two 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). That amplification is lessened by competing actions of n-3 HUFA. Studies of supplemental fish oil have been confounded by timescale factors, topology, pharmacokinetics, pharmacodynamics, adverse events, financial incentives and people’s sense of cause and effect. Two basic aspects of n-3 HUFA action often overlooked 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. Clinicians have successful treatments that decrease CVD deaths. However, the continuing high CVD prevalence indicates neglect of a balanced perspective that can give effective primary prevention with fish oil supplements. Lands B.  Benefit-Risk Assessment of Fish Oil in Preventing Cardiovascular Disease. Drug Saf. 2016 Sep;39(9):787-99. doi: 10.1007/s40264-016-0438-5.  PMID: 27412006

The dietary essential linoleic acid (18:2n-6) has a very narrow therapeutic window as benefit from its moderate physiological actions can easily shift to harmful pathophysiological actions. A rational approach to disease prevention is recognizing and preventing factors that predispose the arachidonic acid cascade to unwanted over-activity. Much evidence for harmful cascade actions was collected by pharmaceutical companies as they developed drugs to decrease the over-activity. A remaining challenge is to prevent nutrient imbalances that predispose the cascade toward unwanted outcomes. Tools have been developed to aid deliberate day-to-day prevention of the propensity for cascade over-activity in ways that can decrease the need for treatment with drugs. Lands B.  Omega-3 PUFAs Lower the Propensity for Arachidonic Acid Cascade Overreactions. Biomed Res Int. 2015;2015:285135. doi: 10.1155/2015/285135.  PMID: 26301244

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. The HUFA balance for different people ranges from 30% to 80% n-6 in HUFA.  While epidemiological studies associate HUFA balance with disease severity, clinical studies that did not examine wide differences failed to confirm the association. Significantly different clinical outcomes between control and intervention groups have been seen when dietary interventions shift the balance of n-3 and n-6 nutrients enough to create a biologically significant difference in the HUFA balance.  Bibus D, Lands B. Balancing proportions of competing omega-3 and omega-6 highly unsaturated fatty acids (HUFA) in tissue lipids. Prostaglandins Leukot Essent Fatty Acids. 2015 Aug;99:19-23. doi: 10.1016/j.plefa.2015.04.005. PMID: 26002802

Current American food has over-abundant omega-6 (n-6) and relatively sparse omega-3 (n-3) nutrients, with an average omega 3-6 balance score near −6. This imbalance causes tissue proportions of about 77% n-6 in HUFA, which links to many chronic health conditions. Americans spend more on treating food-based health conditions than they spend on food. Informed food producers can readily prepare and market new food products with more n-3 and less n-6 nutrients to reverse the current nutrient imbalance and help people maintain a healthy HUFA balance. New functional foods and nutraceuticals can shift financial resources from treating signs and symptoms caused by HUFA imbalance to preventing the nutrient imbalance that causes the need to treat. Clark C, Lands B. Creating Benefits from Omega-3 Functional Foods and Nutraceuticals. Food and Nutrition Sciences, 2015, 6, 1613-1623.   

Conversion of dietary 18-carbon n-3 and n-6 polyunsaturated fatty acids to 20- and 22-carbon highly unsaturated fatty acids (HUFA) is catalyzed by promiscuous enzymes that allow different types of fatty acid to compete among each other for accumulation in tissue HUFA. Serious food-related health disorders, which are made worse by excessive omega-6 actions, can be prevented by eating more omega-3 fats, less omega-6 fats, and fewer calories per meal. Lands B.  Dietary omega-3 and omega-6 fatty acids compete in producing tissue compositions and tissue responses. Mil Med. 2014 Nov;179(11 Suppl):76-81. doi: 10.7205/MILMED-D-14-00149.  PMID: 25373089

Current public advice from the Food and Nutrition Board about essential fatty acids (EFA) has limited recognition of 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 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 n-6 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 preventive nutrition that could beneficially replace current imprecise advice to eat “healthy foods”. Lands B. Historical perspectives on the impact of n-3 and n-6 nutrients on health. Prog Lipid Res. 2014 Jul;55:17-29. doi: 10.1016/j.plipres.2014.04.002. PMID: 24794260

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 signals affect nearly every aspect of human physiology. Similar competitive dynamics convert dietary n-3 and n-6 EFA into HUFA that accumulate in cells and tissues. In contrast, the formation and action of bioactive mediators from HUFA during tissue responses to stimuli tend to have more intense actions with n-6 than n-3 homologs. Both n-3 and n-6 nutrients have beneficial actions, but many chronic health disorders are consequences of excessive actions of tissue n-6 HUFA which are preventable. It is possible to prevent imbalances in dietary n-3 and n-6 nutrients with informed voluntary food choices. Preventing n-3 and n-6 nutrient imbalances on a nationwide scale may have large consequences for the national economy. Lands B. Consequences of essential fatty acids. Nutrients. 2012 Sep;4(9):1338-57. doi: 10.3390/nu4091338.  PMID: 23112921

When people stay healthy, less health care treatments need to be paid. Also, health care treatments are uneconomical and unethical when they only remove signs and symptoms and leave the primary cause unchanged to cause future harm. Neglected preventable causes make massive financial loss in the US. Monitoring imbalances of omega-3 and omega-6 hormone precursors in individuals can increase awareness of and motivation for 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 HUFA balance and quality of life.  Lands B.   Prevent the cause, not just the symptoms. Prostaglandins Other Lipid Mediat. 2011 Nov;96(1-4):90-3. doi: 10.1016/j.prostaglandins.2011.07.003. PMID: 21827870

Traditional health care services have focused more on treatment of signs and symptoms of cardiovascular disease 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 relief from the highest health care treatment costs in the world. It seems unethical and uneconomical to withhold community-wide primary prevention advice and only attend to people with clinical signs of disease. Treatments that remove a sign or symptom without removing the primary cause unethically set a sense of improved health while the unchanged cause that continues to harm 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. It 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 HUFA balance which influences 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. Lands B.   False profits and silent partners in health care. Nutr Health. 2009;20(2):79-89. PMID: 19835105

Effective prevention of the current annual $400 billion losses from atherosclerosis and cardiovascular disease (CVD) will require preventing primary causes rather than just decreasing preventive risk factors (signs and symptoms) produced by the 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. Molecular events connecting diets to death include two modifiable food imbalances. 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. People could 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. Lands B. Planning primary prevention of coronary disease. Curr Atheroscler Rep. 2009 Jul;11(4):272-80.  PMID: 19500490

Credible hypotheses of dietary causes of disease 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 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 design successful prevention of two fatal food imbalances with credible dietary preventive interventions, but organizers and financers to help gather the evidence remain unknown. Lands B.  A critique of paradoxes in current advice on dietary lipids. Prog Lipid Res. 2008 Mar;47(2):77-106. doi: 10.1016/j.plipres.2007.12.001.  PMID: 18177743

Every year, more young people start the slow progressive injury that eventually becomes cardiovascular disease and death. It could be prevented with nutrition education, but medical efforts focus more on treatments for older people than on preventing primary causes of disease in young people. Two simple dietary interventions prevent avoidable risk: (1) Eat more omega-3 and less omega-6 fats, so tissues have less intense n-6 eicosanoid action, and (2) eat less food per meal to lower vascular postprandial oxidant stress. An empirical diet-tissue relationship was developed and put into an interactive personalized software program to inform personal food choices. Lands WE. Dietary fat and health: the evidence and the politics of prevention: careful use of dietary fats can improve life and prevent disease. Ann N Y Acad Sci. 2005 Dec;1055:179-92. PMID: 16387724

Deficits in efforts for primary prevention of cardiovascular disease come from two attitudes of the biomedical community. One involves a bias towards expensive curative/treatment interventions that neglect prevention of initial nutritional causes of disease and death, and the other involves careless logic in interpreting evidence on the etiology of disease and death. Both attitudes are made worse by a widespread wish for simple descriptions of the complex chain of events in disease. For example, attention to cholesterol ignored evidence that nutritional imbalances in expenditure/intake of energy and in n-3 and n-6 fatty acids cause cardiovascular disease. Balancing the few percent of daily calories in n-3 and n-6 nutrients is independent of obesity or blood cholesterol. Effective prevention requires targeting known etiological risk factors that are seldom discussed by health professionals. Death from coronary heart disease comes from acute ischemia and arrhythmia, often following long-term chronic inflammatory vascular damage that predisposes to acute fatal thrombosis and arrhythmia. All three processes involve excessive actions of n-6 autacoids produced from tissue HUFA that come only from foods. Readily corrected imbalances in expenditure/intake of energy and in n-3/n-6 essential fatty acids are preventable causal risk factors with plausible mechanisms contributing to fatal events. Lands WE. Primary prevention in cardiovascular disease: moving out of the shadows of the truth about death. Nutr Metab Cardiovasc Dis. 2003 Jun;13(3):154-64.  PMID: 12955797

The balance of eicosanoid precursors in human tissues differs widely, reflecting voluntary dietary choices among different groups worldwide. An empirical quantitative diet-tissue relationship fits these diverse values. Information about essential fatty acids and eicosanoids to facilitate dietitian education and diet counseling is at the distance learning web site, http:// The site has interactive diet planning software with an empirical equation embedded in it to help evaluate personal food choices in the context of the diet-tissue-disease relationship and other widely recommended dietary advice. Lands WE. Diets could prevent many diseases. Lipids. 2003 Apr;38(4):317-21.    PMID: 12848276

Considering the n-3 fatty acids to be partial agonists relative to n-6 fatty acids helps make a unified interpretation of many controversies about these two types of essential fatty acids. Some research reports illustrate the similarities between these two types and some emphasize the differences, much like regarding a glass of water as half empty or half full. Both n-3 and n-6 types of fatty acids must be obtained through the diet because they are not synthesized de novo by vertebrates. Both types support important physiological and developmental processes, form eicosanoids (prostaglandins, leukotrienes, lipoxins, etc.), are esterified to and hydrolyzed from tissue glycerolipids, and are elongated and desaturated to a variety of highly unsaturated fatty acids (HUFA). However, some nonesterified n-6 acids are vigorously converted to potent n-6 eicosanoids that exert intense agonist actions at eicosanoid receptors, whereas the n-3 acids less vigorously form n-3 eicosanoids that often produce less intense actions. Important physiological consequences follow the inadvertent selection of different daily supplies of these two types of nutrient. Lands WE.  Biochemistry and physiology of n-3 fatty acids. FASEB J. 1992 May;6(8):2530-6.   PMID: 1592205

Traditional dietary patterns in Japan are no longer typical. Current changing conditions give an opportunity to examine how important health conditions associate with the lifestyle changes in dietary total fat, saturated fat, and the balance of n-3 and n-6 fats in the diet.   Lands WE, Hamazaki T, Yamazaki K, Okuyama H, Sakai K, Goto Y, Hubbard VS. Changing dietary patterns. Am J Clin Nutr. 1990 Jun;51(6):991-3.    PMID: 2190465

A non-linear relationship between the aggregation of human platelets and the amount of TXB2 generated requires caution when assessing antiplatelet regimens. The relationship approximates a hyperbola with a roughly linear relationship only for 0 to 70% aggregation and 0 to 50 ng TXB2 per ml of platelet-rich plasma. Using TXB2 formation alone is unlikely to be interpretable without reference to this non-linear property of platelet function. Forty subjects took dietary supplements of 1.8 g or 2.7 g of ethyl eicosapentaenoate (20:5n-3) for four weeks. Reductions of platelet function were clearly evident in 31 of 40 subjects when paired results were examined relative to the recognized hyperbolic relationship. Lands WE, Culp BR, Hirai A, Gorman R.  Relationship of thromboxane generation to the aggregation of platelets from humans: effects of eicosapentaenoic acid. Prostaglandins. 1985 Nov;30(5):819-25.   PMID: 3001834

Neoplastic mast cell tumors were grown in mice which had been raised since birth on a diet with or without supplemental fish oil. The arachidonic acid content of the supplemented tumors was less (3.9 vs. 9.2 mole%) while eicosapentaenoic acid was more (4.5 vs. 0.5mole %) When harvested cells were stimulated with calcium ionophore A23187, they produced lipoxygenase products from the liberated HUFA. Leukotriene B4, B5, C4, and C5 were isolated and characterized by HPLC retention time, ultraviolet absorption spectrometry and mass spectrometry. The relative amounts of arachidonic and eicosapentaenoic acids associated with similar amounts of LTB4 and LTB5 synthesized, suggesting that the intermediate leukotriene (LTA) derivative is made similarly from either n-6 arachidonic or n-3 eicosapentaenoic acids. In contrast, a 10 times greater ratio of n-6 LTC4/LTB4 (2.0) than that for n-3 LTC5/LTB5 (0.16) indicated that reaction of n-6 LTA4 with glutathione was 10 times greater than that for n-3 LTA5.  Murphy RC, Pickett WC, Culp BR, Lands WE.  Tetraene and pentaene leukotrienes: selective production from murine mastocytoma  cells after dietary manipulation. Prostaglandins. 1981 Oct;22(4):613-22.  PMID: 6119740

The effect of altering the relative abundance of n-3 and n-6 prostaglandin precursors by fish oil supplements was investigated using induced myocardial infarction in dogs. Prior to induction, dogs were fed for 36 to 45 days standard dog chow with or without supplemental menhaden oil. Thrombosis and subsequent infarction was induced by electrical stimulation of the left circumflex coronary artery of ambulatory dogs that were monitored by telemetry. Stimulation of control animals increased ectopic beats from less than 10% to about 80%. In contrast, the oil-fed dogs maintained a more normal ECG pattern with less than 30% ectopic beats. The size of infarction in supplemented animals was 3% of the left ventricle compared to 25% in the controls. Dietary supplementation with fish oil may reduce myocardial damage associated with coronary artery thrombosis.  Culp BR, Lands WE, Lucchesi BR, Pitt B, Romson J.  The effect of dietary supplementation of fish oil on experimental myocardial infarction. Prostaglandins. 1980 Dec;20(6):1021-31.  PMID: 7208950

updated November, 2017