Abstract

Dietary fat is our second most important energy-producing macronutrient. It also contains fatty acids and vitamins essential for growth, development, and maintenance of good health. Dietary fat quantity and quality have been subject to tremendous change over the past 10,000 years. This has, together with other man-made changes in our environment, caused a conflict with our slowly adapting genome that is implicated in “typically Western” diseases. Rather than reducing our life expectancy, these diseases notably diminish our number of years in health. Important changes in dietary fat quality are the increased intakes of certain saturated fatty acids (SAFA) and linoleic acid (LA), introduction of industrially produced trans fatty acids, and reduced intakes of ω3 fatty acids, notably alpha-linolenic acid (ALA) from vegetable sources and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fish. The pathophysiological effects of these changes are diverse, but are increasingly ascribed to induction of a proinflammatory state that progresses easily to chronic low-grade inflammation. The latter might affect virtually all organs and systems, possibly beginning at conception, and possibly even prior to gametogenesis through epigenetic alterations. Low-grade inflammation might be a common denominator of the metabolic syndrome and its sequelae (e.g., coronary artery disease (CAD), diabetes mellitus type 2, some types of cancer, and pregnancy complications), some psychiatric diseases (e.g., major and postpartum depression, schizophrenia, and autism), and neurodegenerative diseases (e.g., Alzheimer’s disease, Parkinson’s disease). The long-chain polyunsaturated fatty acids (LCPUFA) arachidonic acid (AA), EPA, and DHA are intimately related to the initiation and resolution of inflammatory responses. The current balance between AA and EPA + DHA is however disturbed by the dominance of AA, which originates from the diet or synthesis from LA. LCPUFA are together with their highly potent metabolites (prostaglandins, thromboxanes, leukotrienes, resolvins, and (neuro)protectins) involved in the functioning of membrane-bound receptors, transporters, ion channels, and enzymes, and also in signal transduction and gene expression. Among their many targets are nuclear receptors which, upon ligation with LCPUFA and their metabolites, function as transcription factors of a variety of genes functioning in many pathways. For instance, the targeted peroxisome proliferators-activated receptors (PPARs) are strategic intermediates in the coordinated expression of proteins with functions in, for example, lipid and glucose homeostasis and inflammatory reactions. Many interventions have been conducted with LCPUFA, especially EPA and DHA, aiming at primary and secondary CAD preventions, improvement of fetal and newborn (brain) development by supplementation during pregnancy or early postnatal life, and in psychiatric diseases. Consensus has been reached that those in CAD and depression are positive, although more large-scale trials are needed. Many recommendations for the intakes of saturated fat, trans fat and EPA + DHA have been issued, notably for CAD prevention, and also for EPA + DHA intakes by pregnant women and for AA, EPA, and DHA intakes by newborns. The ultimate goal might, however, be to return to the fat quality of our ancient diet on which our genes have evolved during the past million years of evolution, while this actually applies for our entire dietary composition and lifestyle, as translated to the culture of the current society.

2.1. INTRODUCTION

Dietary fats and especially their caloric content and individual constituents, such as essential fatty acids (EFA) and fat-soluble vitamins, are indispensable for growth, development, and maintenance of good health. The nutritional value of dietary fats and their fatty acid composition cannot be considered in isolation since they are part of a diet that in its optimal form is balanced to fulfill the nutritional requirements of adults, and, in infants, children, and adolescents, should also be appropriate for growth and development. The corresponding nutrient needs, as defined by the Dietary Reference Intakes (DRIs) for both sexes and the various life stage groups, have been established by authoritative organizations such as the Food and Nutrition Board of the Institute of Medicine (DRI USA, 2008).

The influence of maternal diet prior to conception, during pregnancy and in early life on child development, and adult onset of many diseases is increasingly recognized (Gluckman et al., 2005). Many Nutritional Boards, for example that of The American Heart Association, recommend exclusive breastfeeding for 4–6 months, and, if possible, its continuation to 12 months, because of its beneficial effects on the prevention of obesity and its possible impact on lower blood pressure in later childhood, and on lower blood cholesterol at adult age. Some of these effects may be on the account of better self-regulation of energy intake and taste preference at later ages (Gidding et al., 2005). The period from weaning to a mature diet, usually from 4 to 6 months to 2 years, is characterized by the introduction of complementary foods^* and should be guided by the physiologic and developmental readiness of the infant, nutrient requirements for growth and development, and other health considerations (Butte et al., 2004). Special emphasis is laid on the moderation of the consumption of “kid foods,” which tend to be high in fat and sugar, including excess juice, juice-based sweetened beverages, French fries, and nutrient-poor snacks, and may easily cause the exceeding of energy requirements. For those aged 2 years and older the emphasis is on a diet that primarily relies on fruits and vegetables, whole grains, low-fat and nonfat dairy products, beans, fish, and lean meat, which translates to low intakes of saturated fat, trans fat, cholesterol, and added sugar and salt, adequate intake of micronutrients, and an energy intake and physical activity appropriate to maintain a normal weight for height (Gidding et al., 2005).

After an introduction on the evolutionary aspects of our changing diet during the past 10,000 years and its relation with the development of “typically Western disease,” and stressing the importance of intrauterine and early postnatal diet, this chapter focuses on the influence of LCPUFA^* on development, health, and disease.

2.2. OUR CHANGING DIET FROM AN EVOLUTIONARY PERSPECTIVE

Humans share a common ancestor with the chimpanzee and bonobo that probably lived in East Africa some 6 million years ago. Hominins have since then experienced a tremendous brain growth and assumed an upright position, which coincided with a change from a vegetarian to a hunting-gathering omnivore–carnivore. The oldest Homo sapiens found to date originates from the current Ethiopia and is about 160,000 years old (White et al., 2003). Since about 100,000 years ago humans have started to spread across the whole world to become the only Homo species currently inhabiting this planet. The “Out-of-Africa” Diaspora necessitated adaptation to new conditions of existence. Changes in physical characteristics gave rise to the concept of “race,” which is however better described by “geographical location” of origination as shown by studies of human genetic variation (Rosenberg et al., 2002). The number of new alleles that has been added to H. sapiens’ gene pool since the “Out-of Africa” Diaspora is small compared with the genetic variation that was already present in its founder population. If the total genetic variance is set at 100%, it becomes apparent that 93%–95% of the variance can be ascribed to differences between individuals belonging to a single population within a single race and that the differences between populations within a single race account for only 2%, so that the five races do not differ by more than 3%–5% (Rosenberg et al., 2002).

The vast majority of alleles that have been added to the already existing variance results from the selection pressure that was experienced by the changing environment since 160,000 years ago. They include alleles for protection against sunlight (skin (de)pigmentation, Jablonski and Chaplin, 2000; Harris and Meyer, 2006) and infectious diseases such as malaria (Cserti and Dzik, 2007), small pox, yellow fever, typhus, and cholera (Balter, 2005), and also for new diets such as milk consumption at adult age (lactase persistence, Harris and Meyer, 2006), gluten (grains, Cordain, 1999), and starch-rich diets (amylase copy number variation, Perry et al., 2007). The molecular clock hypothesis estimates that our nuclear DNA changes with an average rate of about 0.5% per million years (1.7 × 10⁻⁹ substitutions/site, year; Ingman et al., 2000). The genuine rate of genomic change is obviously dependent on the actual mutation rate, the magnitude of selection pressure, and other driving forces in population genetics, such as genetic drift (i.e., loss of genes in small populations). There is evidence that the rapidity became increased since the diminishing influence of famine and infection and the concomitant growth of the human population from some 40,000 years ago (Hawks et al., 2007), but basically we remained almost the same as the first H. sapiens, some 160,000 years ago. In other words, genetically, we are for the greater part still adapted to the East African ecosystem on which our genome evolved, with some adaptations since the Out-of-Africa Diaspora. It is clear that any change of environment is capable of introducing new selection pressure, with outcomes ranging from no effect to extinction, but also to an intermediate outcome that confers a loss of number of years in health without major influence on the chance to reach reproductive age. This basic principle of evolution was already noticed by Darwin in 1859.

2.2.1. Conflict between Current Diet and Our Ancient Genome

Since the agricultural revolution (i.e., some 10,000 years ago) we have gradually changed our diet and accelerated these changes from the beginning of the industrial revolution (100–200 years ago). The seven major dietary changes as recognized by Cordain et al. (2005) are summarized in Figure 2.1. Briefly, we have shifted our dietary macronutrient composition toward carbohydrates at the expense of protein, increased the intakes of ω6 fatty acids (notably LA from refined seed oils), SAFA and industrially produced trans fatty acids, decreased our ω3 fatty acid intake (both ALA and those from fish oil), shifted to a carbohydrate-rich diet that contains a high percentage refined carbohydrates with high glycemic indices (e.g., highly processed grains, sucrose, fructose), decreased the intake of certain micronutrients (e.g., folate, vitamin D, magnesium, zinc), shifted toward acid-producing foodstuffs (like meat, grains) at the expense of base-producing counterparts (fruits, vegetables), increased our sodium (salt) intake and reduced our potassium intake, and decreased the intake of fiber.

FIGURE 2.1

The seven crucial nutritional factors that have been changed since the agricultural and industrial revolutions. (Data derived from Muskiet, F.A. et al., Prostag. Leukot. Essent. Fatty Acids, 75, 135, 2006. With permission.)

Table 2.1 compares the EFA intakes from the reconstructed Paleolithic diet with that of a typically Western diet and with current recommendations. Estimates of EFA intakes were calculated for a savanna-like diet (models 1 and 2, Eaton et al., 1998; Eaton and Eaton, 2000; Cordain et al., 2000) with different plant–animal subsistence ratios. In contrast to the savanna diet, the unpublished data of Kuipers et al. (models 3 and 4) assume a shore-based diet in which meat was mixed with fish harboring fatty acid compositions of those living in current Tanzanian lakes and the ocean (Kuipers et al., 2005, 2007). The median intakes (model 3) and their ranges (model 4), indicate that the mixing of fish into the savanna-like Paleolithic diet greatly increases the intakes of the sum of the fish oil fatty acids (EPA + DHA) to a median of 12.05 (range: 3.98–28.7 g/day), while the intakes of ALA and AA in all models are high, and that of LA is low. The calculated high LCPUFAω3 intakes compare well with those of the Eskimo’s who have lifetime high consumption of marine foods (see Section 2.5.1.2). The models were constrained at a maximum intake of 35 en% from protein (Cordain et al., 2000), an intake of more than 1.7 en% LA to prevent biochemical signs of EFA deficiency (Barr et al., 1981) and an (EPA + DHA)/AA ratio above about 2.0. Low values for the latter ratio are related to CAD and neuroinflammatory diseases (Sections 2.5.1.6, 2.5.3.2, 2.5.4.2, and 2.5.4.4). The (EPA + DHA)/AA constraint was calculated from the current recommended intake of 450 mg EPA + DHA/day, while the upper limit of the mean dietary intake of AA from typical Western diets is about 220 mg/day (Section 2.5.1.2, Astorg et al., 2004).

TABLE 2.1

Estimated Intake of EFA from a Paleolithic Diet, as Compared with Intakes from a Current Typically Western Diet, RDAs, AIs, and AMDRs

The EFA and other changes in our diet together with an energy intake that does not match with our current sedentary lifestyle has caused a conflict with our genome that is likely to be at the basis of “typically Western” diseases. The resulting human phenotype centers around the metabolic syndrome,^* which is a risk factor for associated diseases such as cardiovascular disease (CAD), diabetes mellitus type 2, osteoporosis, and certain types of cancer, notably those of the breast, prostate, and colon (Reaven, 2005; WCR/AICR, 2007). Many, if not all, of the polymorphisms^† that have been implicated in Western disease up to now give rise to perfectly normal genes that do not cause disease by themselves and are likely to have been with us since the first H. sapiens. With a generation time of 20–25 years, the nucleotide sequence of our genome could simply not have become adapted to these new conditions of existence. Polymorphisms giving rise to variant proteins with different sensitivities to dietary factors, such as vitamins (Ames et al., 2002), are widespread, and may cause a higher need in the homozygous and occasionally heterozygous states. If the prevalence of these genotypes exceeds 2.5% they are at least partially included into the recommended dietary allowance (RDA) for that dietary factor, which by definition equals the recommended intake for a certain nutrient that is sufficient for 97.5% of the population (Yates et al., 1998). Illustrative are homozygotes for the methylenetetrahydrofolate reductase 677 C → T (Ala222 → Val) allele and protein (MTHFR TT), which compared to MTHFR CT and CC counterparts, require higher folate status for optimal functioning of the variant enzyme. MTHFR TT has a prevalence of about 10%–20% in the white population, but is also widespread among the other races. Such polymorphic genes might better be referred to as “genes sensitive to faulty environment” (i.e., low folate), rather than “disease susceptibility genes.”

The domination of famine during human evolution has shaped our genome to what has been named the “thrifty genotype”^* (Chakravarthy and Booth, 2004; Prentice et al., 2005) by Neel as early as 1962 (Neel, 1999). It is conceivable that basically, we are all carriers of the “thrifty genotype.” This hypothesis seems increasingly proven by genetic analyses, since the alleles with demonstrated risk of obesity in meta-analysis exhibit high frequency and confer low relative risk (Van den Berg, 2008), which might have been predicted from the evolutionary comprehensible phenomenon of high frequency–low penetrance and low frequency–high penetrance (Willett, 2002; The Wellcome Trust Case Control Consortium, 2007). It seems that our genetically determined “survival strategy” turns against us now that we can eat whatever we want and whenever we want, and need little physical activity for food procurement. This, so-called obesogenic environment has never existed in the past, was consequently not part of selection pressure, and genetic adaptations might therefore also not be expected. Consequently, obesity is not a genetic disease, apart from some rare mutations (Farooqi and O’Rahilly, 2006). The conclusion that it is “caused by an interaction between genes and environment” distracts from its causation by our current “faulty” environment and therefore does not carry useful information from a public health perspective. The identification of the underlying genes is nevertheless important from the point of view of health care, since it may help us target treatments in those who have developed disease from underexposure or overexposure to the underlying environmental factor(s).

2.3. IMPORTANCE OF EARLY DIET: THE THRIFTY PHENOTYPE

Intrauterine undernourished or malnourished, so-called programmed, newborns are at risk of some typically Western diseases at adult age, notably when they become exposed to the nutrient-rich postnatal environment and sedentary lifestyle that is characteristic for affluent societies and increasingly so for rapidly developing countries, that is, the “societies in transition” (Prentice and Moore, 2005). This “fetal origins” hypothesis of the early 1990s by Barker (1995, 2007) was initially based on the epidemiological relation between low birth weight and the development of CAD at adult age, but is now known to be associated with many diseases and their risk factors in affluent societies, such as obesity, diabetes mellitus type 2, stroke, osteoporosis, polycystic ovary syndrome, abnormal vascular compliance, endothelial dysfunction, insulin resistance, compromised hypothalamic–pituitary–adrenal (HPA) axis, and schizophrenia (Godfrey and Barker, 2000). More precisely, the hypothesis states that “limiting food resources at a vulnerable time during intrauterine growth and development may cause physical and metabolic adaptations of the fetus that predispose to disease in later life.” The hypothesis is also referred to as the “thrifty phenotype” and the “developmental origins of health and disease” (DOHaD) (Hales, 1997; Wells, 2003; Stocker et al., 2004; Prentice and Moore, 2005). It should, however, be noted that “low birth weight” is a proxy for intrauterine nutrient restriction, since “normal birth weight” does not preclude underdevelopment of particular organs or systems. Normal birth weight refers to quantity, not quality, and can, for example, still be attained if maternal nutrition is adequate in late gestation (Buckley et al., 2005). In addition, the hypothesis is nowadays not limited to the effects of undernourishment, since it has become clear that fetal overnutrition leading to “high birth weight” may exert similar effects (Cottrell and Ozanne, 2008). Such conditions are likely to become more prevalent, since “high birth weight” is clearly associated with disturbed maternal glucose homeostasis, such as occurring in diabetes mellitus type 2 and gestational diabetes.

2.3.1. Evolution and the Thrifty Phenotype

Low birth weight is usually derived from maternal malnutrition, undernutrition, placental dysfunction, or abnormal fetal handling (Godfrey and Barker, 2000). An overview of biological factors influencing prenatal growth and development is shown in Figure 2.2 (Ceelen et al., 2008). Dependent on type, timing, and duration, these insults may compromise growth of those organs developing in the affected time window or preclude the reach of the organism’s genetically determined maximum growth. Mechanistically, the ensuing growth restriction, and notably its hierarchy in terms of which organ becomes affected first, is likely to have an epigenetic^* background aiming at adjusted development of the various organs and systems. Analogous to the “thrifty genotype,” the “thrifty phenotype” is also likely to find its origin in evolution. Dependent on the magnitude of the insult, these adaptations may either be of immediate value to survival (the so-called immediate adaptive response) or improve Darwinian fitness at a later stage of development (the so-called predicted adaptive response; PAR). They are to be distinguished from insults that cause gross pathology or even intrauterine death, such as the central nervous system pathology caused by severe iron, iodine, or folic acid deficiencies, of which the latter is known for its causal relation with neural tube defects. The immediate adaptive response comes with long-term costs in the sense of higher chance of disease development. The PAR is advantageous from an evolutionary point of view, because it allows for better adaptation to the predicted environment and thereby confers a higher chance of survival and reproductive success. Disease may, however, ensue if the predicted environment mismatches with the actual environment. The combination of the thrifty phenotype and a postnatal nutrition-rich environment, might constitute a not-readily observed mismatch between intrauterine and postnatal conditions in humans, that explains much of the epidemiology of Western disease (Bateson et al., 2004; Gluckman et al., 2005, 2007a; Gluckman and Hanson, 2006; Godfrey et al., 2007; Waterland and Michels, 2007; Hanson and Gluckman, 2008; Malina and Little, 2008).

FIGURE 2.2

Biological factors influencing prenatal growth and development. Effect sizes depend on the developmental stage (e.g., organogenesis, fetal period) of the conceptus. (Adapted from Ceelen, M. et al., Fertil. Steril., 90, 1662, 2008. With permission.)

2.3.2. The Thin Fat Baby

Many valuable data with regard to the thrifty phenotype have come from India. Comparison of the body compositions of a 2700 g newborn in India with a 3500 g newborn in the United Kingdom, revealed that the Indian baby has preserved brain volume, but has developed a relatively large adipose tissue compartment at the expense of muscle and visceral organs such as liver, pancreas, and kidneys (Figure 2.3) (Yajnik, 2004). The cord blood insulin and glucose levels of these “thin fat babies” are higher than those of counterparts born in the United Kingdom, while similar signs of insulin resistance are noticeable at the age of 4 and 8 years, especially when they grow fast (Yajnik, 2000). Interestingly, these differences in body composition seem to persist to adult age, since at similar body mass index, East Indians have higher percentage body fat, compared with Caucasians (Deurenberg et al., 1998; Yajnik and Yudkin, 2004). This fat mass is notably located in the abdominal cavity which is a feature of the metabolic syndrome in which low-grade inflammation, insulin resistance, and compensatory hyperinsulinemia are central (Reaven, 2005).

FIGURE 2.3

Body compositions of white Caucasian United Kingdom and East-Indian newborns. The growth retarded Indian baby, also referred to as the “thin fat baby,” has preserved its brain volume and adipose tissue compartment at the expense of muscle (more...)

2.4. POSTNATAL NUTRITION WITH SPECIAL REFERENCE TO FAT

The influence of the postnatal diet on development of typically Western diseases has been studied intensively. Although fat and cholesterol consumption and high serum cholesterol have for long been blamed as the principal causes of the CAD epidemic, we now know that this so-called lipid–heart hypothesis” is at least incomplete and that dietary fat and cholesterol quantities hold questionable relations with CAD. There is no solid evidence that a high intake of fat per se is harmful in terms of CAD, cancer, or obesity in adults and also the influence of dietary cholesterol has been, and is still, exaggerated. For instance, consumption of one cholesterol-rich egg (about 200 mg/egg) daily up to six times per week does not increase risk of CAD or heart failure (Djousse and Gaziano, 2008a,b). The focus is nowadays mostly on fat quality (Lichtenstein, 2003) (see Section 2.4.2), while there is increasing evidence that carbohydrates, especially those with high glycemic indices, and food products with high glycemic loads play important roles in the etiology of obesity, insulin resistance, and CAD, and that a high protein intake reduces obesity risk (Last and Wilson, 2006). Food products with high glycemic loads, especially when consumed in isolation, cause transient hyperinsulinemia (which is associated with CAD) and postprandial hypoglycemia (which is associated with the stimulation of appetite) (Last and Wilson, 2006). Compared with three other diets the low-carbohydrate Atkins diet proved superior for weight loss within a 1 year RCT with overweight premenopausal women (Gardner et al., 2007). It was also shown that isoenergetic diets with high protein (25 en%) or monounsaturated fatty acids (MUFA; 21 en%) have more favorable effects on systolic blood pressure, serum lipid profile and CAD risk, when compared with a diet with 58 en% carbohydrates (Appel et al., 2005). Low-carbohydrate/high-protein diets have by now proven their favorable influence on weight loss (Last and Wilson, 2006), which however does not imply that all of these are healthy or easily maintained (Alhassan et al., 2008). It nevertheless gains acceptance that the for long propagated replacement of SAFA and trans fatty acids with an isoenergetic percentage carbohydrates has unfavorable effects on CAD risk. They might for this purpose better be replaced by unsaturated fatty acids (UFA), protein, or both. Also the messages that vegetable oils are “good” and animal fat is “bad” proved incorrect and so is the notion that all SAFA are “wrong” and that MUFA and polyunsaturated fatty acids (PUFA) are “right.” Categorizing fats into “tropical fats” and “nontropical fats” does not seem to make sense either. There are no “good” and “wrong” naturally occurring fats that have been part of our diet since the first H. sapiens, because nutrition is about the “balance” on which our genome has become to what it currently is.

2.4.2. Fat Quality as Risk Factor

It is widely accepted that atherosclerosis is associated with the consumption of SAFA and trans fatty acids by their ability to increase serum total- and LDL-cholesterol with no effect or decrease of HDL-cholesterol (Gidding et al., 2005). A detailed review on the effects of dietary fatty acids on serum cholesterol showed that isoenergetic replacement of 1 en% carbohydrates with SAFA, such as lauric acid (12:0^*), myristic acid (14:0), and palmitic acid (16:0) increases LDL-cholesterol, but also HDL-cholesterol (Mensink et al., 2003). Stearic acid (18:0) does not influence LDL- and HDL-cholesterol to an appreciable extent. However, lauric acid induces a significant decrease of the total-cholesterol/HDL-cholesterol ratio, which implies that replacement of carbohydrate with the saturated 12:0 lowers CAD risk from at least a theoretical point of view. Replacement of 1 en% carbohydrates with SAFA, cis-MUFA, PUFA, or trans-MUFA does not induce much change in the total-cholesterol/HDL-cholesterol ratio for SAFA, causes a steep decrease for cis-MUFA and PUFA, but produces an increase for trans-MUFA. Replacement of 10 en% of the typical U.S. diet with carbohydrates or a variety of naturally occurring fats or oils would theoretically cause the steepest increase of the total-cholesterol/HDL-cholesterol ratio for carbohydrates and the steepest decrease of this ratio for rapeseed oil, soybean oil, and olive oil (Figure 2.4; Mensink et al., 2003). Taken together, these data suggest favorable effects of reduced carbohydrate consumption and are illustrative for the nuance with regard to the influence of naturally occurring fatty acids, fats, and oils on our serum lipid risk profile. In addition, EPA and DHA have little effects on serum cholesterol, apart from a modest increase of LDL-cholesterol. Their favorable effects on CAD risk are attributed to their antiarrhythmic, antithrombotic, antiatherosclerotic, and anti-inflammatory effects, while they improve endothelial function, and lower both blood pressure and serum triglycerides (Din et al., 2004; Lee et al., 2008; Mozaffarian, 2008).

FIGURE 2.4

Predicted changes in serum total-cholesterol/HDL-cholesterol ratio if a mixed fat constituting 10% of energy in the “average” U.S. diet is isoenergetically replaced by carbohydrates or various fats and oils. (Adapted from Mensink, R.P. (more...)

It has become clear that the dietary fatty acid composition may not only adversely affect serum cholesterol, but also influences coagulation, endothelial function, inflammation, abdominal obesity, insulin sensitivity, development of type 2 diabetes mellitus, and arrhythmias (Erkkila et al., 2008). Such adverse conditions are likely to have been introduced by the increasing intake of SAFA, trans fatty acids and ω6 fatty acids (notably LA) in the Western diet during the past century and the concomitant decrease of the ω3 fatty acids intake from vegetable oils and fish (Figure 2.5; Simopoulos, 1999, 2006). A diet-induced proinflammatory and prothrombotic state may be part of the chronic low-grade systemic inflammation that is associated with the insulin resistance and compensatory hyperinsulinemia of the metabolic syndrome (Reaven, 2005). The current dominance of the ω6 fatty acid series (LA and AA) over those from the ω3 series (ALA, EPA, and DHA) may at least partially be at the basis of this proinflammatory and prothrombotic state (Innis, 2007b; Siddiqui et al., 2008). Low-grade inflammation is emerging as a common feature of the metabolic syndrome (Tilg et al., 1994) and its sequelae, but also of neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis (Skaper, 2008), and also major depression (Leonard, 2007) (see Section 2.5.4.4). The relation with disbalanced ω6/ω3 ratio might find its origin in ω6-mediated aggravation of inflammatory responses in conjunction with insuffficient ω3-mediated compensatory anti-inflammatory responses. Recent research indicates that the inflammation initiation/resolving balance is orchestrated by the proinflammatory actions of prostaglandins and leukotrienes from AA, and the inflammation-resolving actions of the lipoxins from AA, and the resolvins and (neuro)protectins from EPA and DHA (Calder, 2006; Mayer and Seeger, 2008; Serhan et al., 2008). Evidence from both observational and experimental studies indicates that industrially produced trans fatty acids, notably those from LA, may also be proinflammatory by as yet are poorly understood mechanisms (Mozaffarian and Willett, 2007). Other adverse effects of trans fatty acids include a decrease of incorporation of other fatty acids in cell membranes, decrease of HDL-cholesterol and increase of LDL-cholesterol, fatty acid desaturase 2 (FADS2) inhibition, decrease of testosterone, lowering of birth weight, increases of platelet aggregation, lipoprotein (a), body weight, and cholesterol ester-transfer protein, and abnormal morphology of sperm (Simopoulos, 2008).

FIGURE 2.5

Fat intake of hominins and H. sapiens since our common ancestory with the current chimpanzee. Inlays: Reconstruction of H. sapiens Idaltu dated about 160,000 years ago (White et al., 2003), central obesity as a characteristic of the metabolic syndrome, (more...)

2.5. LCPUFA IN HEALTH AND DISEASE

There is good evidence to show that the evolution to H. sapiens took place on an ω3-rich diet from East-African ecosystems that were notably located in places where the land meets freshwater. The sites at which the fossil remains of our ancestors have been discovered are in support of this notion (Gibbons, 2002b), while the Out-of-Africa Diaspora has largely taken place via the coastal lines (Stringer, 2000) also after the crossing of the Bering Strait (Wang et al., 2007). Compared with hunting in the savanna, food from the land–water ecosystems is relatively easy to obtain and rich in iodine, vitamins A and D, and ω3 fatty acids from both vegetables and fish. Each of these nutrients has important functions in brain development and growth. Exploitation of this ecosystem, and its abundant “brain food,” might be at the basis of our remarkable brain growth during the past 6 million years of evolution since our common ancestry with the present chimpanzee. This dietary composition seems somewhat abandoned since the Out-of-Africa Diaspora, since deficiencies of many of these particular nutrients are among the most widely encountered in the current world population (Broadhurst et al., 1998, 2002; Crawford et al., 2001; Holick and Chen, 2008). Iodine is added to table salt in many countries, and margarines and milk have become popular food products for fortification with vitamins A and D. The dietary composition of our ancestors has also become clear from our current (patho)physiology: epidemiological data demonstrated a negative association of fish consumption with CAD (see Section 2.4) and (postpartum) depression (Hibbeln, 1998, 2002), while landmark trials with ALA (de Lorgeril et al., 1999) and fish oil (GISSI-Prevenzione trial, 1999; Lee et al., 2008) in CAD, and with EPA in depression and schizophrenia (Peet and Stokes, 2005) supported the causality of these relations. It has become clear that the intake of the parent EFA and their chain elongation/desaturation metabolites, the so-called LCPUFA (≥20 straight-chain carbon atoms and ≥3 methylene-interrupted cis-double bonds) is important to our health across the entire life cycle, but that their intakes have been subject to tremendous change. This section deals with their (patho)biochemistry and (patho) physiology and specifically concentrates on their role in pregnancy, neonatal nutrition, and psychiatric disease.

2.5.1. (Patho)biochemistry and Physiology of LCPUFA

2.5.1.1. LCPUFA Synthesis, Regulation, and ω3/ω6 Balance

LA (18:2ω6, precursor of the ω6-series fatty acids) and ALA (18:3ω3, precursor of the ω3-series) are the parent EFA for humans (Innis, 1991, 2003). “Essential” implies that the nutrient in question cannot be synthesized to sufficient amounts and therefore needs to be obtained from the diet to prevent development of disease. Most of the dietary LA and ALA is used for energy generation, converted to other compounds or used for structural purposes. Especially LA can become stored to reach high levels in adipose tissue. The parent EFA are also converted to LCPUFA by microsomal desaturation (delta-6 and delta-5 desaturases; also referred to as FADS2 and fatty acid desaturase 1 (FADS1), respectively), microsomal chain elongation, and peroxisomal chain shortening (Figure 2.6). Humans do not possess a delta-4 desaturase, which precludes the direct synthesis of DHA from its precursor 22:5ω3. Direct desaturation is circumvented by initial elongation of 22:5ω3 to 24:5ω3, followed by delta-6 desaturation by FADS2 and a single cycle of beta-oxidation in peroxisomes to yield DHA. The output of this pathway is, however, limited (Muskiet et al., 2004; Burdge, 2006; Williams and Burdge, 2006) as may, for example, be derived from the lower DHA status of vegans compared with omnivores (Fokkema et al., 2000a), and the inability to augment DHA status by supplementation with ALA (Fokkema et al., 2000b) or very high EPA (Horrobin et al., 2003). Supplemental ALA does however increase EPA and 22:5ω3 status (Stark et al., 2008).

FIGURE 2.6

Chain elongation and desaturation pathways of the parent essential fatty acids ALA and LA, and of stearic and palmitic acids. Abbreviations: ALA, alpha-linolenic acid; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; GLA, gamma-linolenic acid; DGLA, (more...)

The sharing of the elongating and desaturating enzymes by ω6 and ω3 fatty acids causes them to compete for conversion into the various LCPUFA. It must however be appreciated that the ω3 and ω6 fatty acids also compete in many other pathways, such as beta-oxidation, incorporation into lipids, release from lipids, conversion into highly active metabolites, and binding to receptors. Circulating AA levels are relatively constant at LA intakes ranging from 3 to 10 en% (Innis, 2007b). Consumption of a high LA diet by healthy adults increases plasma phospholipid LA and decreases EPA with no effect on AA (Liou et al., 2007), suggesting that our current high LA intake contributes to our low EPA/AA ratio. Generally, high EPA and DHA intakes lower AA status in some tissues, erythrocytes (RBC), and circulating lipids (Innis, 2003), but this does not seem to occur to the same extent in all compartments, notably not in the brain. For instance at variable DHA status, DHA and 22:5ω6 exhibit inverse relationships in rat frontal cortex, with little effect on AA (McNamara and Carlson, 2006). AA in the postnatal baboon central nervous system (CNS) seems tightly controlled and much less sensitive to dietary manipulation than DHA, possibly because the pathway for AA synthesis from the abundant LA (by three endoplasmic steps) might be more efficient than the pathway of DHA from the less abundant ALA (by six endoplasmic and one peroxisomal step). Postnatal feeding with formulae without DHA causes a DHA drop in most CNS structures of the baboon infant, which can be prevented by alternative feeding with a formula with DHA (Diau et al., 2005; Brenna and Diau, 2007). Brain LCPUFA profiles exhibit remarkable similarity among different mammals (Tassoni et al., 2008) and the data on the DHA vs. AA relation in animal brain are in line with the limited cross-sectional data from the brains of young infants. These show lower DHA and somewhat higher (Farquharson et al., 1992) or equal (Makrides et al., 1994) AA in children who received infant formula without LCPUFA, compared with counterparts receiving breastmilk (which contains LCPUFA). Nevertheless, the complex interrelationships between the two EFA series puts emphasis on the need of dietary “ω6/ω3 balance” to reach “homeostasis.” The dietary composition producing this “balance” is as yet unknown, but it may be postulated that it is part of our ancient diet, because it is that diet on which our genes evolved.

The regulation of LCPUFA synthesis is complex and notably targets FADS1 and FADS2. Both enzymes are widely expressed in human tissues, notably in liver (Nakamura and Nara, 2004), but also in the brain, placenta, and the mammary gland (Innis, 2005, 2007a,c). The liver enzymes seem major origins of the LCPUFA synthesized from LA and ALA. The contributions of the brain, placenta, and mammary gland enzymes to brain, fetal, and newborn LCPUFA status are uncertain but probably small. For instance, DHA synthesis in the adult rat liver is sufficient to keep brain DHA constant while the brain itself is unable to do so (Rapoport et al., 2007). There are no differences in the capacities to convert ALA to DHA between prematures, term babies, and adults (Innis, 2007a). Women have higher capacity to synthesize DHA, which might be mediated by estrogens (Williams and Burdge, 2006). Compared with LCPUFA synthesized from their parent precursors, there is a clear preference for preformed AA and DHA from the diet for incorporation into brain and other tissues (Lin and Su, 2007; DeMar, Jr. et al., 2008) and for preformed DHA originating from transplacental transfer and milk for fetal and newborn tissue accretion (Innis, 2005). Dietary LCPUFA downregulate LCPUFA synthesis by negative feedback inhibition (Nakamura and Nara, 2004). Insulin stimulates the expression of both enzymes, while it also stimulates expression of delta-9 desaturase (steroyl-CoA desaturase) (Brenner, 2003; Jump, 2004). The latter is the third important desaturase that is notably related to de novo fatty acid synthesis and is, for example, induced in adipose tissue during insulin resistance (Sjogren et al., 2008). Other factors affecting LCPUFA synthesis are various hormones, cofactors like vitamin B₆ and zinc, and inflammatory stimuli (Nakamura and Nara, 2003; Jump, 2004). Downregulation of LCPUFA synthesis by dietary LCPUFA, the presumed high LCPUFA intakes from our ancient diet (Table 2.1), the occurrence of FADS1 and FADS2 polymorphisms with lower activities (see Section 2.5.1.7), and our difficulty to synthesize DHA suggest that the LCPUFA synthesis machinery has only been used during long periods with low LCPUFA intakes, such as during famine or limited availability of animal foods. The low AA level and higher ratio between dihomo-gamma-linolenic acid and AA (DGLA/AA) in plasma phospholipids of Greenland and Danish Eskimos, compared with Danes, has led to the suggestion that Eskimos may have low FADS1 activity. This would render them obligate carnivores who, similar to cats, are in need of a dietary LCPUFA source (Gibson and Sinclair, 1981).

The FADS1 and FADS2 genes are located in a head-to-head orientation on chromosome 11. The proximity of their promoters suggests that they might be coordinately controlled by common regulatory sequences but this has not been demonstrated as yet. The FADS2 promoter contains binding sites for the (ligated) PPAR-alpha (see Section 2.5.1.5) and the active form of the sterol regulatory-binding protein-1c (SREBP1c). Binding of the ligated PPAR-alpha and SREBP-1c proved necessary for FADS2 transcription and this was found to occur notably during LCPUFA demand, such as in EFA deficiency. Consequently, PPAR-alpha and SREBP-1c may collectively be considered as our “LCPUFA sensors” (Nakamura and Nara, 2004). The strong feedback control on LCPUFA synthesis by LCPUFA is mediated by reduced FADS2 transcription secondary to the reduction of the active form of SREBP-1c. This mode of regulation implies that excess of dietary LCPUFA from either the ω3 or ω6 series may shut off synthesis of both LCPUFA series, which is a strong argument for the need of dietary LCPω3/LCPω6 balance, and may play a role in the AA lowering effect of DHA supplementation (Nakamura and Nara, 2004). Transcription of the opposite strand of FADS1, named reverse-FADS1, gives rise to an antisense transcript that is able to bind to complementary sequences of the FADS1 transcript and thereby lowers or even switches off FADS1 translation. Fasting and refeeding with a high glucose fat-free diet and administration of fish oil were found to be triggers for the induction of the antisense regulator of FADS1, which probably exerts its action by accelerating FADS1 mRNA degradation or interference with its translation (Dreesen et al., 2006). One-carbon metabolism is linked to LCPUFA metabolism and status by the methylation of phosphatidylethanolamine (PE) to phosphatidyl-choline (PC) via the phosphatidylethanolamine-N-methyltransferase (PEMT) pathway (Watkins et al., 2003; Umhau et al., 2006). PC may also become synthesized via the CDP-choline pathway, but the resulting species carry less AA and DHA than those deriving from the PEMT pathway. In addition, hyperhomocysteinemia was recently shown to influence LCPUFA synthesis by the silencing of FADS2 in mouse liver. The mechanism was by hypermethylation of the FADS2 promoter and was accompanied by higher PE, and lower AA and DHA in liver phospholipids (Devlin et al., 2007).

2.5.1.2. Dietary LCPUFA Sources and Intakes

Both LA and ALA are predominantly derived from vegetable oils. The various edible oils differ widely in LA and ALA contents and their ratio. Sunflower oil and corn oil are, for example, high in LA, and soy bean oil and especially linseed oil have (much) higher ALA/LA ratio. Meat, eggs, and poultry are rich sources of AA, while EPA and DHA are derived notably from fish, meat, and eggs. The EPA and DHA contents and ratios in fish are dependent on their position in the food chain and the composition of the phytoplankton from which these LCPω3 ultimately originate. Freshwater fish may synthesize their own EPA and DHA from the appropriate precursors (Sargent, 1997). There are little differences in reported intakes of LA in Western countries, which are typically in the 11–18 g/day range. Also AA intake is rather constant, amounting to 160–230 mg/day for men and 120–200 mg/day for women. This may, together with the constancy of AA across a wide range of LA intakes (3–10 en%), explain the constancy of AA status in Western countries (Liou et al., 2007; Innis, 2007b). In contrast, there are wide differences in ω3 fatty acid intakes and the resulting ω3-status. ALA intake in Western countries is typically 1.2–1.8 g/day, but is up to 1.7–2.2 g/day in Japan. The LA/ALA ratio amounts to 4–8 in Japan, 6–10 in most Western countries, and >13 in South-European countries (Astorg et al., 2004), but has also been estimated at 15–16 for the typical Western diet (Simopoulos, 2001). Notably LCPω3 intake is highly variable among countries. EPA + DHA intakes in Japan are 1.0–1.5 g/day for men and 0.7–1.1 g/day for women. They amount to 0.7–1.0 g/day in Norway and 0.7 g/day in Spain, while relatively low intakes have been reported for the United States (210–240 mg/day), Germany (215–315 mg/day), and Australia (175 mg/day) (Astorg et al., 2004). Vegetarians consume 30 mg DHA/day (Haggarty, 2004). Lifetime LCPω3 intakes by Eskimos has been estimated at 14 g/day, while the intake in Denmark was 3 g/day (Feskens and Kromhout, 1993). The latter figures compare favorably with our estimates for an East-African freshwater-based diet of our ancestors (see Table 2.1). Higher LCPω3 intakes than the 450 mg/day as currently advised would not only provide maximal effects on arrhythmia risk, but also on the lowering of serum triglycerides, heart rate and blood pressure, and on thrombosis risk (Mozaffarian, 2008). Docosapentaenoic acid (22:5ω3) intake seems to occur notably from meat, with total daily intakes of 85–105 mg in Japan, 60–80 mg in Sweden and France, and 71 mg in Australia (Astorg et al., 2004; Howe et al., 2006). Gamma-linolenic acid (GLA) is abundant in borage, black current, and evening primrose oils (Kapoor and Huang, 2006).

2.5.1.3. EFA and LCPUFA Function

The parent EFA (notably LA) and LCPUFA are building blocks of the membrane phospholipids of all cells. They contribute to the membrane’s physicochemical properties and thereby the functions of membrane-bound receptors, transporters, ion channels, enzymes, and other membrane-bound biochemical processes, such as those involved in signaling pathways. LA has a clear structural function of its own. As building block of ceramides in our skin, LA contributes to the skin’s barrier function to limit transepidermal water loss. In contrast to LA, ALA gets stored in our body to only a limited extent. ALA is largely degraded to acetyl-CoA for the generation of energy or de novo synthesis of SAFA, MUFA, and cholesterol, for example, in the brains of the fetus and newborn (“recycling,” Cunnane et al., 2006). LA and LCPUFA are also stored in adipose tissue, but especially AA exhibits preference for phospholipids (Nelson et al., 1997) perhaps to control AA release and subsequent conversion to its highly potent eicosanoids. EFA make up 20% of brain dry weight, including about 6% for AA and 8% for DHA. Brain levels of LA and ALA are low. DHA and AA are notably located in the synaptosomes, where AA is of special importance as a second messenger in (synaptic) signal transduction and DHA provides the needed fluidity for appropriate neurotransmitter receptor activity. DHA is the major fatty acid in the structural phospholipids of the retinal photoreceptor outer segment membrane, where its fluidity is essential to accommodate the extremely rapid conformational changes of rhodopsin (Kurlak and Stephenson, 1999). Part of the retinal phospholipids is composed of PE, phosphatidylserine (PS), and PC that carry two DHA acyl moieties. Brain AA and DHA reach highest levels in gray matter and especially those areas involved in motor activities (Diau et al., 2005). DHA’s role in neurodevelopment has been grouped into effects on gene expression, mono-aminergic neurotransmission, protection against apoptotic cell death, and neurite outgrowth from the cell body (Innis, 2007a). DHA also has an important function in spermatozoa, where DHA’s unique structure contributes to motility (Tavilani et al., 2006). Both AA and DHA are important to maintain a healthy endothelium of our cardiovascular system (Calder, 2004). The importance of AA/DHA balance in myocardial phospholipids to preserve a low arrhythmogenic eicosanoid profile has been emphasized (McLennan and Abeywardena, 2005). LCPUFA synthesis from parent precursors may also be subject to “programming” (see Section 2.3). A diet high in SAFA given to pregnant rats caused reduced AA and DHA and increased LA and ALA in the aorta of their offspring, suggesting poor conversion of parent EFA to LCPUFA. These abnormalities coincided with vascular dysfunction and persisted to adulthood (Ghosh et al., 2001).

2.5.1.4. Eicosanoids, Resolvins, Protectins, and Others

LCPUFA are precursors of highly potent metabolites that are involved in various signaling processes. After their release from membrane phospholipids by phospholipase A₂ (PLA₂) some of the C₂₀ LCPUFA, that is, AA (20:4ω6), DGLA (20:3ω6), and EPA (20:5ω3) may become converted to eicosanoids (prostaglandins, thromboxanes, leukotrienes, hydroxyeicosatetraenoic acids, and epoxy-eicosatrienoic acid), which is a family of lipid mediators synthesized via the cyclooxygenase (COX1 and COX2), lipooxygenase (LOX), and the cytochrome P450 pathways. DGLA gives rise to prostaglandins, prostacyclins, and thromboxanes of the one-series (e.g., PGD₁, E₁, F_1α), AA leads to the two-series (PGD₂, E₂, F_2α, PGI₂, TXA₂) and EPA to the three-series (PGD₃, E₃, F_3α, PGI₃, TXA₃). AA is also converted to the four-series leukotrienes (LTA₄, B₄, C₄, D₄), while EPA gives rise to the five-series leukotrienes (LTA₅, B₅, C₅, D₅). These mediators are involved in a variety of occasionally opposing functions such as smooth muscle contraction, fever induction, augmentation of vascular permeability, pain, vasodilation (PGE₂), vasoconstriction and platelet aggregation (TXA₂), vasodilation and platelet aggregation inhibition (PGI₂), contraction of smooth muscles in the respiratory tract, vessels, and intestine, leukocyte chemotaxis, increased vascular permeability, enhanced local blood flow, and release of lysosomal enzymes and reactive oxygen species (LTB₄) (Calder, 2006).

The eicosanoids from EPA are believed to be less potent than those of AA. For instance, TXA₃ is a weak agonist of TXA₂ in inducing vasoconstriction and platelet aggregation, while PGI₂ and PGI₃ exert similar vasodilating and antiaggregating effects. Also LTB₅ is much less potent in eliciting neutrophil chemotaxis than LTB₄. Eicosanoids from AA are widely considered to be proinflammatory, whereas those from EPA are weakly inflammatory or anti-inflammatory. This must however be viewed upon as a generalization, since newly identified mediators of AA are not only involved in the initiation, but also in the resolution of inflammatory reactions. Prostaglandins and leukotrienes are intimately involved in the initiation of inflammation following its triggering by, for example, microbial infection, surgical trauma, hypoxia, and reperfusion injury. The outcome is progression to chronic inflammation, scarring and fibrosis, or complete resolution. Resolution is accompanied by a switch to the production of lipid mediators with anti-inflammatory and proresolving properties. These mediators include AA-derived lipoxins, which function as stop signals and are followed by the appearance of EPA-derived resolvins from the E-series and DHA-derived resolvins from the D-series and protectins (named neuroprotectins when generated in the neural tissue). Mediators from EPA and DHA stimulate resolution and the return to homeostasis (Serhan et al., 2008; Serhan and Chiang, 2008).

2.5.1.5. LCPUFA and Gene Expression

LCPUFA are not only important structural elements of membranes. Together with their eicosanoid products and other fatty acids, they are also firmly implicated in gene expression. For example, dietary LCPUFA are ligands of PPARs and suppress the expression of SREBPs, nuclear transcription factor kappa-B and others. These are nuclear transcription factors that can be considered as main switches in the coordinated expression and repression of a variety of (key) enzymes and proteins in intermediary metabolism, thermoregulation, energy partitioning, growth and differentiation, and inflammatory responses (Duplus and Forest, 2002; Clarke, 2004; Jump, 2004; Lapillonne et al., 2004). PPARs are among our bodily “lipid sensors” and, importantly, they constitute a link between lipid and glucose homeostasis, and inflammation (Figure 2.7). The serum triglyceride lowering effect of fish oil fatty acids is, for example, attributable to their interaction with PPAR-alpha. Recent data show that DHA and EPA play key regulatory roles in the coordinated expression of genes involved in glycolysis, de novo lipogenesis, fatty acid elongation, desaturation, and oxidation in the liver. They target many nuclear receptors that are part of at least three major transcriptional regulatory networks controlling hepatic carbohydrate and lipid metabolism, that is, by activation via the PPARs/retinoid X receptor (RXR) heterodimer and suppression of the nuclear abundances of SREBP-1 and the carbohydrate regulatory element-binding protein (ChREBP)/Max-like factor X (MLX) heterodimer. DHA weakly activates PPAR-alpha and strongly suppresses SREBP-1, while its hepatic retroconversion metabolite EPA is a strong PPAR-alpha activator. PUFA of both the ω3- and ω6-series suppress ChREBP/MLX abundance (Jump, 2008). Because of their strategic role in many metabolic and signaling routes PPARs are logical targets for drugs. For instance, the fibrates for serum triglyceride lowering are agonists of PPAR-alpha, while the insulin sensitivity increasing properties of the thiazolidinediones (glitazones) are based on their agonistic action toward PPAR-gamma. PPAR-gamma has been referred to as “the ultimate thrifty” gene, because of its ability to stimulate lipogenesis in the liver and adipose tissue (Auwerx, 1999). The unique 1300–1400 ų Y-shaped cavity that constitutes part of the PPAR lipid-binding domain may be at the basis of their promiscuous ligand-binding characteristics, but recent data suggest that fish oil fatty acids and notably their derivatives are among the most powerful naturally occurring PPAR ligands (Deckelbaum et al., 2006; Bragt and Popeijus, 2008; Itoh and Yamamoto, 2008; Gani and Sylte, 2008; Gani, 2008).

FIGURE 2.7

Role of PPARs in gene expression and repression. Ligated PPARs heterodimerize with the ligated RXR to interact with a PPAR response element (PPRE). This interaction leads to the coordinated expression of many proteins involved in a variety of pathways. (more...)

2.5.1.6. EFA and LCPUFA Deficiency and Marginality

Clinical signs of ω6 fatty acid shortage include growth retardation, reproductive failure, fatty liver, and a dry (scaly) skin that is characterized by augmented transdermal water loss. Deficiency of ω3 fatty acids may cause dysfunctioning of the central nervous system, including cognitive dysfunction and impaired vision. Biochemically, EFA deficiency (i.e., of both LA and ALA) gives rise to the accumulation of Mead acid (20:3ω9), because of the action of the chain elongation/desaturation system on the competing oleic acid (18:1ω9) (Figure 2.6). The order of substrate affinity of FADS2 is ALA > LA > oleic acid, which also explains the decrease of DHA with reciprocal increases of LCPω6, notably 22:5ω6 and to a lesser extent 22:4ω⁶ and AA, in isolated ALA deficiency. DHA may be conditionally essential (Muskiet et al., 2004), because of the difficulty by which it is synthesized and the relation of low DHA status with disease. “Conditionally essential” refers to a need of a dietary source during circumstances at which demand exceeds synthesis, such as during rapid growth, augmented nutrient loss, or declining synthesis, as for example, occurring in fetuses, young children, adolescents, pregnancy, lactation, and at advanced age. Age-dependent cutoff values for RBC 20:3ω9 (marker for EFA deficiency), RBC 22:5ω6/20:4ω6 (marker for ω3 deficiency), and RBC 22:5ω6/22:6ω3 (marker for ω3/DHA marginality and deficiency) have been proposed (Fokkema et al., 2002). Disbalances between AA, EPA, and DHA may change the ratio between EPA- and AA-derived eicosanoids with concomitant pathophysiological effects. For instance, there is a positive relation between the AA/EPA ratio in the platelets of different ethnic groups and the percentage of CAD deaths (Simopoulos, 2008). Competition between AA and EPA + DHA occurs to a large extent in compartments in which LCPUFA seem to have limited functionality apart from membrane flexibility or transport, such as RBC and plasma phospholipids. Consequently, measurements of LCPUFA in these compartments provide sensitive parameters for LCPUFA status assessment, of which the outcome is, however, as yet poorly defined in terms of pathophysiological consequences or disease risk. LCPUFA contents of RBC are considered a good reflection of brain LCPUFA (Makrides et al., 1994; van Goor et al., 2008a). The omega-3 index, that is, the sum of EPA and DHA in RBC, has been proposed as a risk factor for sudden cardiac death and may also serve as a fish oil treatment goal. An omega-3 index of >8 g/100 g RBC fatty acids (g%) is associated with 90% lower CAD risk, as compared with an index of <4% (von Schacky and Harris, 2007; von Schacky, 2008).

Biochemical and possibly clinical evidence of EFA deficiency is often present in protein-energy malnutrition (PEM). Typical symptoms in PEM, like skin changes, impaired resistance to infections, impaired growth rate, and disturbed mental functioning and development may be explained by coexisting EFA and LCPUFA deficiencies (Smit et al., 2002). Clinically apparent EFA deficiency in Western countries is rare. The sporadic cases are mostly based on heritable or acquired diseases that cause, or are accompanied by, poor gastrointestinal fat absorption.

2.5.1.7. Inborn Errors and Polymorphisms

Demonstrated genetic defects in LCPUFA synthesis comprise FADS2 deficiency and peroxisomal beta-oxidation defects such as those occurring in the Zellweger syndrome and adrenoleukodystrophy (Jump, 2004). The FADS2 deficiency was caused by an insertion in its transcription regulatory region, leading to symptoms consistent with EFA deficiency with low AA and DHA. The clinical symptoms, such as corneal ulceration, feeding intolerance, growth failure, photophobia, and skin abnormalities, improved upon administration of AA and DHA (Williard et al., 2001; Nwankwo et al., 2003). Patients with generalized peroxisomal disorders such as present in Zellweger’s syndrome, have profound brain DHA deficiency. DHA supplementation improves their vision, liver function, muscle tone, and social contact, but the treatment should be initiated as soon as possible after birth (Martinez et al., 2000; Martinez, 2001).

At least 18 polymorphisms have been demonstrated in the gene cluster of FADS2 and FADS1. These polymorphisms exhibit a high degree of linkage disequilibrium and are accompanied by diminished FADS1 and FADS2 activities. Carriers of the minor alleles had higher LA, 20:2ω6, 20:3ω6, and 18:3ω3, together with lower 18:3ω6, AA, 22:4ω6, EPA, and 22:5ω3 in their serum phospholipids. The underlying allele(s) explained 28% of the interindividual serum phospholipid AA variability (Schaeffer et al., 2006). Polymorphisms of FADS2 were also found to influence the association between breastfeeding and higher IQ. Children carrying the investigated major allele who received breast milk had higher IQ compared with counterparts receiving infant formula. Those carrying the major allele benefited more from breastmilk than children carrying the minor allele, and this observation did not seem related to maternal genotype (Caspi et al., 2007). Recently we showed that the minor allele of a FADS1 polymorphism is associated with lower RBC AA in pregnant women and that this genotype is sensitive to further AA lowering following DHA supplementation (Dijck-Brouwer et al., 2008). The polymorphisms of FADS1 and FADS2 are clear examples of the many “disease susceptibility genes,” which do not cause disease by themselves, but only at unfavorable environmental conditions (here: low LCPUFA intakes). Their seemingly widespread occurrence might be taken as a testimony that the LCPUFA intakes from our ancient diet have been of sufficient magnitude to confer Darwinian fitness to their carriers.

2.6. CONCLUSIONS

H. sapiens has evolved on a diet that was high in ALA from vegetable sources, rich in AA, EPA, and DHA from a land–water ecosystem (including (lean) fish) and contained low LA, SAFA, and no trans fatty acids from industrial sources. We have, however, gradually changed this diet from about 10,000 years ago and accelerated these changes from about 100–200 years ago. These, but also other, dietary changes are firmly implicated in the risk of typically Western diseases. Some of the relations, for example, the association of ALA and fish oil with CAD and LCPω3 with depression, have proven their causalities in intervention trials. Evolutionary medicine, and perhaps common sense, teaches us that we might have to return to the composition of the diet on which our genes have evolved. For this, we need rethinking of the very basics of “homeostasis” and avoidance of the vicious cycle that is initiated by taking observations from Western societies as a basis of dietary recommendations and lifestyle in general. Traditionally living societies may provide us with clues for absolute standards for human homeostasis, but unfortunately many of these have meanwhile become dependent on food programs with typically Western approaches (e.g., high carbohydrates), or adopted a (quasi) Western lifestyle in general. It may be questioned whether definite answers will come from the expensive RCT approaches of single nutrients, since these require large study numbers, long observation periods, elucidation of dose–response relationships, and investigation of numerous interactions with other nutrients (for example: one-carbon metabolism and LCPUFA). A combination of data from traditionally living societies, (patho)physiological insight, anthropometrics, archeology, genetics, nutrigenomics, and classical trials may lead to cleverly designed RCTs to answer the question on what diet our genes have evolved and what diet consequently promotes our health at best. The lessons from such studies might especially be relevant to early nutrition, because of its importance to development and the increasingly recognized relation between early development and the risk of disease at later life.

ABBREVIATIONS

AA

arachidonic acid

AI

adequate intakes

ALA

alpha-linolenic acid

AMDR

acceptable macronutrient distribution range

BMI

body mass index

CAD

coronary artery disease

ChREBP

carbohydrate regulatory element-binding protein

CNS

central nervous system

COX1 and COX2

cyclooxygenases 1 and 2

DGLA

dihomo-gamma-linolenic acid

DHA

docosahexaenoic acid

DOHaD

developmental origins of health and disease

DRIs

dietary reference intakes

EFA

essential fatty acids

En%

energy %

EPA

eicosapentaenoic acid

FABP

fatty acid-binding protein

FADS1

fatty acid desaturase 1 (delta-5 desaturase)

FADS2

fatty acid desaturase 2 (delta-6 desaturase)

FATP

fatty acid-transfer protein

GDM

gestational diabetes mellitus

GLA

gamma-linolenic acid

GR

glucocorticoid receptor

HDL

high-density lipoprotein

HPA

hypothalamic–pituitary–adrenal

LA

linoleic acid

LCP and LCPUFA

long-chain polyunsaturated fatty acids

LDL

low-density lipoprotein

LOX

lipoxygenase

MLX

Max-like factor X

MTHFR

methylenetetrahydrofolate reductase

MUFA

monounsaturated fatty acid

PAR

predicted adaptive response

PC

phosphatidylcholine

PDAT

pathobiological determinants of atherosclerosis in youth

PE

phosphatidylethanolamine

PEM

protein-energy malnutrition

PEMT

phosphatidylethanolamine-N-methyltransferase

PLA₂

phospholipase A₂

PPAR

peroxisomal proliferators-activated receptor

PS

phosphatidylserine

PUFA

polyunsaturated fatty acid

RAR

retinoic acid receptor

RBC

erythrocytes

RCT

randomized controlled trial

RDA

recommended dietary allowance

RXR

retinoid X receptor

SAFA

saturated fatty acid

SREBP

sterol regulatory element-binding protein

UFA

unsaturated fatty acid

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Footnotes

*

Any energy-containing foods that displace breastfeeding and reduce the intake of breast milk.

*

Long-chain polyunsaturated fatty acids are straight-chain fatty acids with ≥20 carbon atoms and ≥3 double bonds in the methylene-interrupted cis configuration.

*

The metabolic syndrome, also referred to as the insulin resistance syndrome, is a combination of four frequently occurring symptoms, i.e., high blood pressure, disturbed glucose homeostasis, dyslipidemia, and overweight. The syndrome confers high risk of diabetes mellitus type 2, cardiovascular disease, and many other typically Western diseases. Microalbuminuria is a symptom that is also considered to be part of the metabolic syndrome by some.

*

Thrifty genotype hypothesis: limiting food recourses have in the past favored alleles that promote efficient bodily storage of energy reserves. In conditions of plentiful nutrition, this genotype predisposes to disease. Thrifty phenotype hypothesis: limiting food resources cause physical and metabolic adaptations of the fetus that, when mismatched predisposes to disease in later life.

*

The extent to which an organism is adapted to or able to produce offspring in a particular environment.

†

Homeostasis is the “integration of, and the balance between, physiological functions.” It refers to optimal interaction between environment and our genome: “our nature in balance with nurture.”

*

Epigenetics is the study of the changes in gene expression that occur without changes in DNA sequence. These changes are inherently unstable, but stable during mitosis (by which a liver cell remains a liver cell) and occasionally during meiosis (in which case phenotype is transmitted to the next generation). Epigenetics is at the basis of the phenotypic differences between a liver cell and neuron carrying the same genome. The environment transmits instructions to the genome through epigenetics to keep our phenotype perfectly adapted at both short and middle-long term.

*

Fatty acids are denoted as a:bωc, in which a is the (usually even) number of straight chain carbon atoms, b the number of double bonds in the methylene-interrupted cis configuration, and c the number of atoms from the methyl end to the first double bond.

†

Polymorphism refers to differences in DNA sequences that occur with ≥1% frequency in the population. A mutation has a frequency <1%.