Foreword

By the time that you read this foreword, essential fatty acids in your tissues will have already had profound effects on your body's development and health. Knowing that all that's past is prologue, the authors of this collection of reviews assembled knowledge from their past discoveries to set the stage for readers to anticipate another wave of discovery about essential fatty acids (EFA). For 70 years, a growing body of information illumined ways in which n-3 and n-6 fatty acids maintain health and also act in disease. The essential actions of these fatty acids in physiological and behavioral functions occur through three different modes of acyl chain interaction: specific lipid-protein actions in membrane function; specific lipid-protein actions inducing gene expression; and specific receptor-mediated eicosanoid signaling (see Figure 1). When any of these interactions is influenced differently by the n-3 or n-6 arrangement of double bonds in the essential acid, it produces an important consequence of daily food choice. Voluntary food choice is important in health maintenance because the relative abundance of n-3 and n-6 acids in each person's tissues depend on the daily supply. To help people decide whether they wish to make different food choices in the future, the authors address some very complex processes that underlie simple terms like "seizure threshold," "immune function," "retinal function," or "learning behavior." Even now, there are uncertainties about the degree to which the three modes of EFA action in Figure 1 mediate these phenomena. Throughout the 23 chapters and 2078 citations in this book, the authors give information on physiological consequences of dietary EFA supply to help readers evaluate the impact of n-3 and n-6 acid supplies on health maintenance and disease prevention.

Dietary EFA

Tissue F"'

n-3/n-6 Sp n-3/n-6 Lipid-Protein Gene Regulatory Complex n-3/n-6 Sp

Tissue Physiology

Clinical Status

Fig. 1. Essential fatty acids in diets and disease.

THE "DRIFT" IN SUPPLIES OF EFA

For all essential nutrients, a dietary supply is the sine qua non of their action. Chapter 1 points to the general change in intake of EFA over the past centuries that has produced adverse effects on tissue abundances with resultant undesired physiologic and public health outcomes. Negative health consequences of this apparently accidental drift in relative intakes are now seen for different populations. Appendix I of Chapter 1 gives readers clear recommendations for corrective levels of dietary intakes of n-3 and n-6 acids. Chronic inattention to the simple principle that dietary supplies affect tissue abundances of EFA has also led to nearly all experimental animal models in drug development to have excessive n-6 eicosanoid signals with little moderation by n-3 eicosanoid signals. Such polarized experimental models are useful in developing patented pharmaceuticals for treating the consequences of excessive n-6 abundances in tissues. However, measurements in animals fed such imbalanced diets may give little insight into an effective nutritional strategy for preventing the onset of the pathology in the first place. Readers may want to consider the relative abundance of the essential fatty acids in the various foods they routinely eat. To help identify palatable foods that can maintain relative tissue levels of n-3 and n-6 highly unsaturated fatty acids (HUFA) at whatever level desired, readers can use a convenient interactive software program, KIM (Keep It Managed), that is accessible through the website http://ods.od.nih.gov/eicosanoids. Knowledge about the different supplies of EFA in common food servings (over 9000 are listed) seems certain to affect future voluntary dietary choices of well-informed people.

Competition in Maintaining Tissue EFA

The abundant dietary 18-carbon EFA compete vigorously for the limited space conserved for long-chain HUFA in tissue lipids. This competitive metabolism creates reciprocal changes between these acids in tissues. Also, when essential n-3 and n-6 supplies are limited, n-7 and n-9 HUFA accumulate in their place. Chapters 6 through 11 explore these competitions with a focus on healthy perinatal development. These chapters extend beyond the 40-yr-old quantitative evidence of hyperbolic competitive interactions between the n-3 and n-6 acids for elongation, desaturation, and incorporation into tissue lipids (Mohrhauer and Holman, 1963a,b). After reading these chapters, readers might enjoy re-examining that seldom-discussed evidence of competitive hyperbolic metabolic processes for both 18:2n-6 and 18:3n-3, which have midpoints near 0.1 percent of ingested calories (Mohrhauer and Holman, 1963a, b as confirmed by Lands, 1991). Clearly, the effective midpoint for maintaining tissue HUFA is far below the dietary supply now common in the United States.

Bioequivalence is an important concept addressed in several chapters because the highly conserved tissue HUFA are formed from 18-carbon homologs more abundant in the diet. The quantitative competitions among n-3 and n-6 HUFA in the liver, plasma, and visceral tissues parallel, but quantitatively differ from, those in the brain and retina where DHA dominates. Throughout this book, authors lead readers to recognize a special ability of brain and nervous tissue to sequester DHA, illustrating important brain/body differences in EFA dynamics. Tissue abundances of EFA maintained in response to dietary supplies are readily measured by gas chromatography, and extensive efforts were made to predict plasma proportions produced from dietary intakes (e.g., Lands et al., 1992). As a result, the proportion of plasma phospholipid total HUFA that is n-6 HUFA has a predictable relationship to the various dietary EFA supplies. This biomarker of intake (% n-6 HUFA in total HUFA) also relates to the probable intensity of n-6 eicosanoid signaling when the tissue is stimulated. However, despite some progress in estimating tissue EFA, estimating their probable actions along all three modes in Figure 1 remains a major challenge for authors and readers alike.

Preformed docosahexaenoate (DHA) has a 4- to 20-fold greater relative efficacy (or bioequivalence) over linolenic acid (LNA) as substrate for accumulating as brain DHA during perinatal development. Chapter 6 reviews the kinetic data from primates to strengthen the recommendation of including at least a modest supply of DHA in infant formulas to aid brain development. Discussion of the low levels of LNA in brain tissue may reflect the predominance of phosphoglycerides in brain lipids known to differ from triacylglycerols by accumulating linolenate but little LNA. We still have no explanation for how tissue triacylglycerols accumulate LNA while the metabolically related phosphoglycerides do not! Recent advances in evaluating the supply of DHA to the nervous system are noted in Chapter 7. The authors conclude that much ingested LNA is not available for synthesis of DHA, and that elongation and desaturation events in the liver must be accompanied by biosynthetic activity in brain and nervous tissue to maintain adequate DHA levels in those tissues.

Radiolabeled long-chain fatty acids help quantify EFA incorporation rates, turnover, and half-lives and imaging brain phospholipid metabolism in vivo. Chapter 8 notes that the rapid entry of plasma non-esterified fatty acids into brain acyl-CoA pools may be adequate to meet any increased neuronal demands as long as plasma DHA levels are sufficient. Half-lives for turnover of some fatty acids in phosphatidyl inositol and phosphatidyl choline of brain were around 3 h (although that for DHA in phosphatidyl choline was 22 h). The results indicate that incorporation of arachidonate into brain lipids is stimulated by the muscarinic agent, arecoline, and diminished with chronic lithium treatment. Chapter 9 focuses attention on how oxidation and the reuse of acetyl-CoA units (carbon recycling) diverts LNA from its elongation and desaturation to long-chain n-3 HUFA. Carbon recycling is described as a process that decreases the bioavailability of the n-3 fatty acids needed for neural development. Most dietary LNA is completely oxidized for energy even in rapidly growing young animals, and less than 10% seems available for DHA synthesis and esterification in the suckling rat. A three- to four-fold higher oxidation of LNA in the early postnatal period makes carbon recycling more active in neonates than adults.

Readers can find an interesting aspect of brain development in Chapter 10. Astrocytes may provide to neurons 22:6n-3 produced from the 20:5n-3 that had been made by cerebroendothelial cells from 18:3n-3 acquired from plasma. If multicellular transfers are needed to provide neuronal DHA, much more needs to be known about control of this intercellular transport. The authors illustrate ways in which interpreting the nonlinear responses of brain DHA to dietary abundances continues to challenge researchers studying DHA supply and conservation. Until those dynamics are better understood, the functional and behavioral consequences of these nonlinear responses seem certain to remain equally nonlinear and puzzling. Readers will find valuable quantitative insight in Chapter 11, which re-examines bioequivalence during the rapid regain of DHA in primate brain phospholipids during recovery from a dietary n-3 fatty acid deficiency. The extensive results with rhesus monkeys indicate the existence of mechanisms in the brain to conserve HUFA and to manage rapid, reciprocal competitive changes in n-3 and n-6 HUFA. The authors describe analyses of brain and retina EFA that parallel (but quantitatively differ from) analyses of the easily obtained plasma and red cells, which have some quantitatively predictable relations to dietary supplies (Lands et al., 1992). The overall results give clear support that the concepts in the preceding chapters about the reversible, reciprocal changes as n-3 and n-6 HUFA compete for limited space are likely transferrable to human conditions.

Tissue Physiology as Proof of EFA Importance

Vitamins and hormones were identified in the early 20th century by their impact on growth and physiology. Burr and Burr (1929, 1930) identified the n-3 and n-6 EFA when they restored normal physiology to young animals on fat-free diets. Poor overall growth, irregular ovulation, scaly skin, tail necrosis, renal degeneration, and water loss could then be better interpreted. In addition, subnormal testicular development was restored by either dietary EFA or by injected gonadotropin (Greenberg and Ershoff, 1951). Now we can ask which of the three modes in Figure 1 underlie EFA support of the needed pituitary hormone production. Similar questions can address the inadequate dermal integrity that led to greater water loss during EFA deficiency. When researchers used a water rationing protocol to study growth with EFA, a clear difference between n-3 and n-6 nutrients was seen (Thomassen, 1962) that was not apparent when the water supply and humidity were adequate (Burr et al., 1940). Overall, three general physiologic processes seem supported more effectively by n-6 than n-3 EFA: dermal integrity and water balance; renal function; parturition. Readers may see in Chapters 2, 22, and 23 tantalizing clues to mechanisms for those different physiologic outcomes. Eczema and watery stools were clear biomarkers of insufficient EFA for human infants, and they were 50% prevented by about 0.07 % calories as linoleate (Hansen et al., 1963). A later meta-analysis (Cuthbertson, 1976) noted that EFA symptoms in human infants are completely prevented by less than 0.5% of calories as linoleate. Such low thresholds are similar to the 0.3% calories of EFA that proved adequate for growing rats (Mohrhauer and Holman, 1963a,b), supporting the concept that EFA metabolism and physiology are quite similar in rats and humans (Lands et al., 1992).

To help readers interpret body fluid homeostasis, Chapter 22 describes possible roles for n-3 EFA in ways that extend beyond past results with water balance. In addition, new information on mediators of energy homeostasis extends beyond past results on modulating growth hormones and cytokines. Whenever physiologic processes are differentially influenced by n-3 and n-6 EFA, then possible strategies for preventive nutrition can be developed. Chapter 23 illustrates ways in which EFA fit into our expanding awareness about the "information traffic" that integrates the body's nervous system, immune system, and endocrine system to maintain health. The authors note that mechanisms for differential modulation of stress hormones or cytokines by n-3 and n-6 EFA may involve either membrane fluidity, oxidized eicosanoid signaling, or regulation of gene expression. Any successful approach to possibly preventing a disorder will need monitoring with biomarkers that reflect health imbalances prior to the full expression of the clinical disorder that requires treatment. As current choices of traditional foods are now being extended with new "functional foods" to help maintain a balance of n-3 and n-6 EFA, we can expect more nutritional efforts to prevent or diminish the severity of some diseases. Clinicians familiar with the symptoms and methods of treating disorders must share with nutritionists and dietitians an interest in finding useful biomarkers that can properly assess the success of prevention efforts.

Biomarkers of Complex EFA-mediated Events

Many chapters address specific processes that help readers evaluate biomarkers useful in health maintenance and disease prevention. For example, Chapter 3 explores ways that DHA suppresses the expression of VCAM-1, E-selectin, and ICAM-1 on the cell surface, and normal and neoplastic leukocytes exhibit diminished adhesion through the interactions of integrins and selectins. DHA also suppresses expression of major histocompat-ibility II molecules. In contrast, arachidonate increased adhesion of human blood leukocytes to endothelial cells. As in other chapters of this book, readers are challenged to discern which of the three modes of interaction in Figure 1 regulate the cellular events. In Chapter 4, the effects of essential fatty acids on shifting the voltage dependence of voltage-regulated ion channels are noted as affecting seizure thresholds in animals. The discussion of ion channels extends the important finding (Kang and Leaf, 1994) that many polyunsaturated fatty acid soaps can diminish arrhythmia, but arachidonate can also exacerbate it in a manner dependent on n-6 eicosanoid formation. Release of a mixture of HUFA from tissue phospholipids can give direct anti-arrythmogenic and indirect arrythmogenic actions (Li et al., 1997). The relative proportions of n-3 and n-6 HUFA that had accumulated in the tissue prior to a physiologic challenge are clearly important to tissue responsiveness.

Aging is accompanied by altered cytokine expression and release during a progressive shift in relative abundance of Th1, Th2, and CD5+ cells and decline in immune function, which Chapter 5 describes in detail. This chapter provides readers an opportunity to explore how the three different modes of EFA interactions in Figure 1 might participate in altering cytokine-mediated physiology in aging. This background may then be extended to the continually appearing reports on how EFA and their oxidized products regulate expression of genes for cytokines (e.g., Wallace et al., 2001) and metabolic mediators (e.g., Clarke, 2001). Chapter 14 examines disturbances of EFA metabolism during neural complications of diabetes to help readers interpret the reported decreases in arachidonoyl species of phospholipids. Eicosanoid imbalances were indicated for this condition when a cyclooxygenase inhibitor blocked the EFA-supported improvement in nerve conduction velocity and blood flow. Chapter 15 describes another disorder that affects EFA metabolism. It is linked to defects in protein import into peroxisomes by peroxins. The important role of peroxisome enzymes in providing DHA from its docosapentaenoate precursor gives a rationale for DHA therapy in these conditions, which is described in some detail. Chapter 16 extends beyond information in Chapter 4 as it describes diverse effects of fatty acids and ketones on neuronal excitability, exploring their implications for epilepsy and its treatment. The appearance of potentially toxic fatty acid ethyl esters as non-oxidative metabolites of ethanol is reviewed in Chapter 17.

Although the formation is not selective for EFA, these products represent an intriguing biomarker of alcohol exposure.

EFA in Vision, Learning, and Behavior

An outstanding integrated view of DHA actions in vision and brightness discrimination, ranging from acyl chain packing to learning events, is in the combined information of Chapters 2, 12, and 13. Chapter 2 describes how the active form of the visual G- protein-coupled receptor, metarhodopsin II, is modulated by membrane phospholipid acyl chain packing (sometimes referred to as "fluidity"). An increased bilayer area per headgroup of the polyunsaturated phospholipid is associated with more favorable kinetic coupling of the signaling components and is also linked with an increased permeability to water. The authors noted that di-18:3-PC is five times as permeable to water as 18:0,18:1-PC and 18:0,22:6-PC is four times as permeable as 18:0,18:1-PC. Readers may imagine hundreds of other G-protein-mediated systems in which the principles developed for DHA actions with rhodopsin may be extended to signaling systems throughout the body. This concept is advanced further in Chapter 12, which extends beyond phos-pholipid interactions with rhodopsin to describe detailed kinetics of electroretinogram waveforms and how they are used to explore possible roles of omega-3 polyunsaturated fatty acids in photo pigment activation kinetics. Careful interpretation of results on electrophysiologic signals from photoreceptors led the authors to suggest that DHA is not essential for neural function, but is needed to avoid subtle neural anomalies and produce optimal function. The important action of retinal pigmented epithelium in recycling photoreceptor components with interreceptor retinoid binding protein also depends on DHA levels, providing an indirect means by which DHA abundance can affect vision. Thus, DHA deprivation provides a puzzling mixture of neural impairments perhaps due to altered receptoral mechanisms.

Extending beyond previous information, Chapter 13 explores how performance in the brightness discrimination learning test is impaired by a relative n-3 EFA deficiency. Experimenters observed diet-dependent differences in behavior as a complex outcome of retinal function and conditioned appetitive behavior. In recovering full learning behavior, the experimenters showed an expected competition by high dietary linoleate, which decreased the efficacy of n-3 EFA supplements. Also, the observed decreased turnover of DHA-rich brain ethanolamine phospholipids during n-3-deficient conditions may functionally relate to decreased neurotrophin and synaptic vesicle densities in rat hippocampus, a brain area important to learning and memory. Thus, these three chapters on vision and learning introduce key concepts that may help interpret the behavioral and cognitive phenomena described in Chapters 18 through 21. Dramatic cross-national data in Chapter 18 associate seafood and n-3 EFA supply with psychiatric disorders including major depression, bipolar affective disorder, postpartum depression, hostility and homicide, and suicide. A more positive clinical efficacy of EFA over DHA raises the possibility that these disorders may have an imbalance in specific oxygenated eicosanoids that mediate receptor signaling or gene expression rather than having inadequate membrane DHA levels. Chapter 19 reviews possible disorders of phospholipid metabolism in schizophrenia, affective disorders, and neurodegenerative disorders, and Chapter 20 describes use of eicosapentaenoic acid as a potential new treatment for schizophrenia. Chapter 21 continues exploring the importance of DHA in optimal cognitive function by describing several rodent models that measure learning and motivation. The overall results support continued interest in providing some DHA to infants to ensure adequate neurologic development. Readers of this book will find many reasons to re-examine future food choices for themselves and their families.

William E. M. Lands, pud

References

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Burr GO, Brown JB, Kass JP, Lundberg WO. Comparative curative values of unsat urated fatty acids in fat deficiency. Proc Soc Exp Biol Med 1940; 44:242-244.

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Greenberg SM, Ershoff BH. Effects of chorionic gonadotropin on sex organs of male rats deficient in essential fatty acids. Proc Soc Exp Biol Med. 1951; 78:552-554.

Hansen AE, Wiese HF, Boelsche AN, Haggard ME, Adam DJD, Davis H. Role of linoleic acid in infant nutrition. Clinical and chemical study of 428 infants fed on milk mixtures varying in kind and amount of fat. Pediatrics 1963; 31:171-192.

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Lands WEM. Dose-response relationships for 3/ 6 effects. In Simoupoulos AP et al., eds. Health Effects of 3 Polyunsaturated Fatty Acids in Seafoods. World Review of Nutrition and Dietetics, Vol. 66, pp.177-194. Karger, Basel, 1991.

Lands WEM, Libelt B, Morris A, Kramer NC, Prewitt TE, Bowen P, Schmeisser D, Davidson MH, and Burns JH. Maintenance of lower proportions of n-6 eicosanoid precursors in phospholipids of human plasma in response to added dietary n-3 fatty acids. Biochem Biophys Acta 1992; 1180:147-162.

Li Y, Kang JX, Leaf A. Differential effects of various eicosanoids on the production or prevention of arrhythmias in cultured neonatal rat cardiac myocytes. Prostaglan dins 1997; 54(2):511-530

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Keep Your Weight In Check During The Holidays

Keep Your Weight In Check During The Holidays

A time for giving and receiving, getting closer with the ones we love and marking the end of another year and all the eating also. We eat because the food is yummy and plentiful but we don't usually count calories at this time of year. This book will help you do just this.

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