Fig. 4.2 Origins and metabolism of polyunsaturated fatty acids in the foetus. The maternal diet contains a mixture of n-6 and n-3 parent and long-chain polyunsaturated fatty acids (LCP), which will vary widely among species and individuals. After digestion and absorption of the dietary lipids, the re-esterified fatty acids are transported in the maternal plasma as lipoproteins (Chapter 5) and incorporated into maternal tissues, e.g. adipose tissue and liver. Non-esterified fatty acids (NEFA) are released from adipose tissue stores (stage 1 in the figure; also see Chapter 3). The liver exports fatty acids as triacylglycerols in very low density lipoproteins (VLDL; stage 2 in figure) into the maternal plasma. The maternal face of the placenta contains a lipoprotein lipase (LPL) (stage 3; see also Chapters 3 and 5), which releases NEFA from VLDL. The placenta is permeable to NEFA (stage 4). The human placenta contains minimal desaturase activity and stage 5 is probably not a significant source of LCP. Parent polyunsaturates and LCP are transported to the foetal circulation (stage 6) and the foetus can convert a proportion of the parent polyunsaturates into LCP (stage
established that the amounts of 18:2n-6 and 18:3n-3 and of their elongation/desaturation products in the mother's diet influences the fatty acid composition of the developing foetus. Desaturation activity is present in developing foetal brain and liver (Fig. 4.2, reaction 7), so that the foetus may not be totally dependent on a supply of long-chain PUFA (LCPUFA) from the mother (Fig. 4.2, reaction
6). There is, however, little evidence for placental desaturase activity in simple-stomached animals, so that reaction 5 in Fig. 4.2 is unlikely to provide significant amounts of LCPUFA.
Concentrations of all lipoprotein classes increase in the maternal circulation during pregnancy, a process that is mediated by the sex hormones. A lipoprotein lipase has been discovered in human placenta. This is consistent with the hypothesis that during hyperlipidaemia of pregnancy, release of fatty acids by placental lipoprotein lipase could generate substrates for synthesis of lipids by the foetus. The transfer of intact lipoproteins by a receptor-mediated pathway has not been demonstrated but cannot be ruled out. Placental lipopro-tein lipase is present on the maternal, but not on the foetal, side of the placenta and hydrolyses very low density lipoproteins, but apparently not chylomi-crons. Perhaps this constitutes a mechanism for ensuring a flow of fatty acids from mother to foetus, rather than in the reverse direction. It may also allow the mother to control the fatty acids available to the placenta since VLDL are supplied by synthesis in the mother's liver, whereas chylomicrons derive from dietary fat (Section 5.2.3).
In simple-stomached animals, arachidonic and some other LCPUFA are present in higher concentration in foetal than in maternal plasma and in foetal tissues than in foetal plasma. Arachidonic acid seems to be selectively incorporated and trapped into placental phospholipids for export to the foetal circulation. The term 'biomagnification' has been coined for a process in which the proportion of long-chain polyunsaturates increases in phospholipids progressing from maternal blood, to cord blood, foetal liver and foetal brain. Such a biomagnification process probably incorporates the combined effects of placental fatty acid uptake, selective protection of specific fatty acids against P-oxidation and selective direction of fatty acids into membrane or storage lipid biosynthesis.
The study of foetal conservation of essential fatty acids in ruminants is extremely rewarding since the availability of essential fatty acids to the mother is severely limited by rumen hydrogenation (Section 2.2.6). The ratio of 20:3n-9/20:4n-6 in foetal lamb tissues is 1.6. In simple-stomached animals, a value of this ratio above 0.4 is a biochemical marker of essential fatty acid deficiency, as will be explained in Section 18.104.22.168. By 10 days after birth, the ratio falls to 0.4 and by 30 days to 0.1. These values are well within the normal range despite the extremely low concentration of linoleic acid in ewe's milk (0.5% of energy). Ruminants are, therefore, able to conserve linoleic acid with supreme efficiency. Sheep placenta transfers linoleic acid at a relatively slow rate, but has a very high A6-desaturase activity by comparison with non-ruminants, providing the major source of arachidonic acid for the foetus. This metabolite is concentrated into glycer-ophospholipids whereas the linoleic acid precursor is in higher concentration in the triacylglycerols. This molecular compartmentation has the effect of conserving arachidonic acid and directing it into membranes.
In some species, reserves of fatty acids are already being built up in the foetus. For example, the development of human fat cells begins in the last third of gestation and at birth a baby weighing 3.5 kg has, on average, 560 g of adipose tissue. Guinea pigs are also born with a large amount of adipose tissue whereas, in contrast, pigs, cats and rats are born with little or none. There is a remarkable parallelism between the placental permeability to non-esterified fatty acids and the ten dency to accumulate adipose tissue by the foetus, suggesting that an important source of foetal fat reserves is derived from circulating maternal lipids. The adipose tissue composition of the foetal and new-born fat will, therefore, reflect the fatty acid composition of the maternal diet as illustrated in Table 4.4.
A large proportion of the long-chain polyunsaturated fatty acids synthesized or accumulated during the perinatal period is destined for the growth of the brain, of which 50% of the acyl groups may consist of 20:4n-6, 22:4n-6, 22:5n-6 and 22:6n-3. As with adipose tissue, there are large species differences in the time at which birth occurs in relation to the extent of brain development. The peak rate of brain development occurs in guinea-pigs in foetal life; in the rat, post-natally; while in man and pig it reaches a peak in late gestation and continues after birth. It has been suggested that transfer from the placenta is the major source of LCPUFA for the human foetal brain, but the experimental difficulties of demonstrating this in man are enormous. Because of their remarkable similarity to man in the timing of brain development and its lipid composition, pigs have been used as models. Long-chain derivatives of linoleic acid increase in brain from mid-gestation to term. Little linoleic acid, however, accumulates until birth,
Table 4.4 Influence of the fatty acid composition of the mother's dietary fat on the fatty acid composition of adipose tissue in new-born guinea-pigs (g per 100 g total fatty acids)
Maize oil Beef tallow
Fatty acid Maternal diet Adipose tissue Maternal diet Adipose tissue
Others 2 5 12 1
when its concentration increases threefold while the concentrations of its elongation/desaturation products remain constant. By labelling experiments with [l-14C]linoleic acid in vivo, it has been shown that linoleic acid is metabolized to LCPUFA by piglet brain and liver throughout the perinatal period. The contribution of the liver was many-fold greater than the brain at all stages. Whether foetal tissues can supply all the needs of the nervous system for LCPUFA without the need for the maternal transfer of intact LCPUFA is still to be resolved. In regard to maternal transfer, it has been proposed that an intracellular «-fetoprotein, derived from maternal plasma «-fetoprotein may play a role in delivering LCPUFA to foetal brain. It binds fatty acids avidly, especially the LCPUFA such as 20:4n-6 and 22:6n-3. Indeed plasma non-esterified 22:6n-3 seems to be almost exclusively transported on «-fetoprotein despite the quantitative predominance of albumin.
An outstanding feature of the composition of brain phospholipid is its remarkable consistency, irrespective of species or diet. The concentrations of the parent essential fatty acids are extremely low (18:2n-6, 0.1-1.5% and 18:3n-3, 0.1-1.0%) while arachidonic (20:4n-6) and docosahexaenoic (22:6n-3) acids predominate at 8-17% and 13-29%, respectively in all species (Table 4.5).
In contrast to the conservative lipid composition of brain, the liver lipids exhibit much greater variation. The parent essential fatty acids are present in much greater concentrations than they are in brain and there are major differences in the elongation/ desaturation products. For example, 22:5 is the major n-3 fatty acid in the liver lipids of ruminants and other herbivores while 22:6n-3 predominates in the carnivores and omnivores. Fatty acids of the n-6 family usually predominate in liver phosphogly-cerides, even when the dietary intake is in favour of the n-3 fatty acids. Thus, zebra and dolphin, both species that have an overwhelming excess of n-3 fatty acids in the diet, attain a preponderance of n-6 acids in the liver phosphoglycerides (Table 4.5).
Table 4.5 Principal polyunsaturated fatty acids of the liver and brain phospholipids of zebra and dolphin
Food fatty acids n-6/n-3
Liver fatty acids (g per 100 g total fatty acids)
Brain fatty acids (g per 100 g total fatty acids) 18:2n-6 1
Data are taken from Crawford, M.A., Casper N.M. and Sinclair A.J. (1976) Biochem. Physiol., 54B, 395-401. The zebra's food polyunsaturates, both n-6 and n-3 are mainly 18C and the dolphin's 20C and 22C. Of the liver and brain fatty acids, only the principal polyunsaturates are shown for clarity. Figures are rounded to the nearest whole number so that components contributing less than 0.5% of total are not recorded. Note the preponderance of n-6 polyunsaturates in the liver lipids of both species despite the dietary excess of n-3 polyunsaturates and a preponderance of long-chain n-3 polyunsaturates in the brain, with virtually none of the parent acids (18:2n-6,18:3n-3).
At birth, quite large changes in lipid metabolism occur. Whereas the foetus had relied extensively on glucose from which to synthesize (non-essential) fatty acids and triacylglycerols, the sole source of nutrition for the new-born is milk from which about 50% of energy comes from fat. The enzymes of fatty acid synthesis are suppressed and the baby's metabolism becomes geared to using fat directly from the diet.
The lipid composition of human milk is therefore the main factor that determines the availability of lipids for the breast-fed baby's development, especially in respect of the essential fatty acids. Triacylglycerols comprise about 98% of the total lipids in milk and provide most of the required linoleic and a-linolenic acids. Although the glycero-phospholipids represent only about 1% of total milk lipids, they provide about 50% of the long-chain n-3 and n-6 PUFA in milk. The fatty acid composition of human milk (and indeed that of any simple-stomached animal) is highly variable since it is strongly influenced by the fatty acid composition of the mother's diet. However, the milk and dietary fatty acid compositions are not related in a linear manner because the maternal adipose tissue stores also make a contribution to milk fatty acid composition. Table 4.6 illustrates this variability and also compares the composition of human milk with that of cow's milk, which provides the base for most commercial infant formulas. Women eating a vegetarian diet tend to have higher concentrations of 18:2n-6 and 18:3n-3 in their milk. Concentrations
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