Linoleic acid deficiency effects

FIGURE 3-7 Pathways for the interconversion of brain fatty acids. Palmitic acid (16 0) is the main end product of brain fatty acid synthesis. It may then be elongated, desaturated, and/or P-oxidized to form different long chain fatty acids. The monoenes (18 1 A7, 18 1 A9, 24 1 A15) are the main unsaturated fatty acids formed de novo by A9 desaturation and chain elongation. As shown, the very long chain fatty acids are a-oxidized to form a-hydroxy and odd numbered fatty acids. The polyunsaturated fatty acids are formed mainly from exogenous dietary fatty acids, such as linoleic (18 2, n-6) and a-linoleic (18 2, n-3) acids by chain elongation and desaturation at A5 and A6, as shown. A A4 desaturase has also been proposed, but its existence has been questioned. Instead, it has been shown that unsaturation at the A4 position is effected by retroconversion i.e. A6 unsaturation in the endoplasmic reticulum, followed by one cycle of P-oxidation (-C2) in peroxisomes [11], This is illustrated in the biosynthesis of DHA (22 6, n-3) above. In severe essential fatty acid deficiency, the abnormal polyenes, such as 20 3, n-9 are also synthesized de novo to substitute for the normal polyunsaturated acids. 

Documented effects The fruits of this species are an official source of polyvitamins. Preparations (extracts, syrups, candies, pills, etc.) are used treat hypo- and avitaminosis (particularly vitamin C deficiency) as weU to treat diseases related to vitamin deficiency. The fruits are used as a component in an anti-asthmatic mixture. Oil from the seeds is used to treat bums, dermatosis, and radiation exposure. Ascorbic acid and an oil extract Karotolin (containing carotenoids, vitamin E, and linolic acid) are isolated from the pericarp. Karotolin is used to treat trophic skin ulcers, eczana, erythrodermia, and other skin diseases (Khalmatov et al. 1984). 

The perturbation of the incorporation of linoleic add metabolites into mammary gland lipids by CLA metabolism may lead to the hypothesis that CLA is able to create a mild arachidonic acid deficiency condition, in particular in the mammary tissue which is composed mainly of neutral lipids. In fact, because CLA and some of its metabolites are preferentially incorporated into neutral lipids (15), unlike linoleic acid, which is instead incorporated mainly into phospholipids, the preponderance of neutral lipids in the mammary tissue renders the competition between these two fatty acids more favorable toward CLA. It has been demonstrated that mammary tumorigenesis requires essential fatty acids, and eicosanoid inhibitors are able to reduce tumor incidence in experimental models (22). CLA, likely by decreasing the supply of arachidonic acid and inhibiting eicosanoid formation through its metabolites, may counteract arachidonic acid-derived eicosanoid action. Because the decrease of arachidonic acid, CLA metabolite incorporation, TEB density, and tumor incidence correlated with the (XA dietary intake, we can speculate that TEB density could also be modulated by eicosanoids. More data are required, however, to substantiate this hypothesis and to identify which eicosanoid(s) may be responsible for such effects. 

Linoleic and linolenic acids cannot be synthesized in the body. They are considered essential because a lack of them in our diets leads to deficiency symptoms. Total essential fatty acid (EFA) deficiency (both -6 and -3 fatty acids) causes reduced growth, reproductive failure and dermatitis (Burr and Burr, 1929,1930). These symptoms are prevented or reversed by feeding linoleic acid. Linolenic acid is partially effective at preventing or reversing these symptoms but is not specifically required (Holman, 1968). 

Studies in the mid 20th century identified the effects, in rats, of essential fatty acid deficiency (Table 5). Biochemically, the disease is characterized by changes in the fatty acid compositions of many ceU membranes whose functions are impaired (see British Nutrition Foundation, 1992 Gurr et al., 2002 for further details). One of the striking features of essential fatty acid deficiency in rats is skin dermatitis and water loss (see Mead, 1984). Epidermal lipids are rich in ceramides. The fatty acyl substituent in these is linoleic acid linked via its carboxylic acid group to the terminal methyl carbon of another fatty acid (34 1 n-9) to generate an extremely long-chain (52 carbons) stmcture. 

In animals, certain unsaturated fatty acids, such as linolenic or linoleic acids, are essential dietary components. Whether these compounds can be synthesized by man has not been determined, but since they are widely present in fats ordinarily consumed, deficiency seems an unlikely possibility. In dogs, there is evidence for a need of fat above that necessary to relieve specific effects of essential fatty acid deficiency (Chapter 7). This may be true in other species, including man. 

Most of the evidence points to the fact that the effectiveness of fats in counteracting the dermatitis caused by pyridoxine deficiency is proportional to the unsaturation, i.e., presumably to the EFA content. This explanation would account for the fact that lard is effective in alleviating pyridoxine deficiency, since it is ordinarily relatively high in arachidonic and linoleic acids, whereas butter, which has a relatively low content of EFA, is somewhat less efficacious. Schneider (1940) ascribed the low antidermatitis potency of rancid butter to the destruction of the antidermatitis factor (later identified as linoleic acid) during the course of rancidification. 

All of the principal components of the EFA are capable of curing pyridoxine deficiency. According to Quackenbush et al. (1942a) linoleic acid is the most effective of the three principal EFA in clearing up the deficiency symptoms due to the lack of pyridoxine. Salmon (1938) found that the methyl esters of linoleic and linolenic acid are less effective... 

The most convincing proof of the linoleate —> arachidonate conversion is based upon balance experiments involving the content of arachidonate in the tissues when linoleate is fed, as compared with the values in control experiments. The supplementation of fat-deficient rats with corn oil (which contains linoleate but no arachidonate) was found to increase markedly the tetraenoic acid content of liver, kidney, heart, and brain (Rieckehoff et cd., 1949). Even before the availability of the spectrophoto-metric method of analysis for the polysaturated acids, Ellis and Isbell (1926a, 1926b) found evidence of the appearance of arachidonic acid in the pig upon the ingestion of linoleic acid. Nunn and Smedley-MacLean (1938), and also Smedley-MacLean and Hume (1941) both presented additional evidence of the appearance of arachidonate in fat-deficient rats following the administration of linoleate. Widmer and Holman (1950), in a study of the effects of fatty acids in the diet on the synthesis of the EFA, confirmed the transformation of linoleate to arachidonate in the rat. 

Linoleic and arachidonic acids are the most effective of the acids in clearing up the skin symptoms resulting from pyridoxine deficiency or from fat deficiency. Quackenbush and co-workers (1942a) are of the opinion that linoleic acid is more effective than linolenic acid as an antidermatitis factor. In line with this result. Burr et al. (1940) reported that com oil (which has no linolenic acid) is more potent in preventing the skin disorders of fat-deficient animals than is linseed oil (which is relatively rich in linolenic acid at the expense of linoleic acid). In fact, the ability of natural fats to counteract the skin disorders has been found to be in proportion to the linoleic acid content of the diet. According to Richardson et al. (1941) methyl arachidonate and methyl linoleate are equally effective in the treatment of the dermatitis produced by vitamin Be deficiency. 

The cod liver oil proved to be the critical component of the diet. Substitution by com oil made the diet nontoxic, and crude linoleic acid was approximately as effective. The eclamptic disease could be prevented by treating the animals with a-tocopherol or lettuce before the toxic diet was given, or by adding these materials to the eclamptogenic diet. Apart from a possible toxic effect of the vitamin D, it is also possible that the oil itself has a toxic effect. It is known that highly unsaturated acids are present which do not have the activity of the essential unsaturated fatty acids, because they have cis-trans and trans-trans configurations instead of the active cis-ds form. Even deficiency of the essential unsaturated fatty acids may be promoted. The crude linoleic acid, which was not quite as active as corn oil, may contain about 50% of the inactive cis-trans configura-tion(s). The vitamin E content of the com oil is probably important also. 

Much of what is known about skin scaliness in EFA-deficiency originates from the work of Basnayake and Sinclair who found that when rats were given EFA-deficient diets they grew at reduced rates, within a few weeks scaliness of the feet and tail developed, and transepidermal water loss (TEWL) rose by a factor of 10. When EFA was reintroduced to the diet the abnormalities disappeared, that is, the condition was reversible. We have shown that skin abnormalities of the EFA-deficient rat may be reversed also by topical application of linoleic acid, and this is as effective as feeding. Within five days of rubbing sunflower seed oil (a rich source of linoleic acid) onto the dorsal skin of deficient rats, TEWL was restored to normal, more rapidly than the scaliness was healed. 

Cats are unusual among mammals in that neither linoleic nor a-linolenic acid alone is sufficient to protect against the effects of fatty acid deficiency these animals require arachidonic acid in their diets because they lack the desaturases that insert double bonds at positions 6,12 and 15. 

Finally a few remarks should be made about essential fatty acid (EFA) deficiency (section 5.2.2). Linoleic acid is the precursor of the eicosanoids, leukotrienes, prostaglandins, thromboxanes and related compounds (section 3.4). Until recently it was thought that the classic skin symptoms resulting from a deficiency were due to a lack of eicosanoids. However, the specific role of n-6 acids (such as linoleate) as opposed to n-3 acids (such as a-linolenate) in membrane fluidity and their function cannot explain their essentiality. For example, aspirin ingestion which effectively prevents prostanoid formation does not result in the appearance of EFA-deficiency symptoms. It is also generally accepted that at least some cell lines in culture do not have an EFA requirement - thus suggesting that EFAs are not essential for the formation and function of cellular membranes in general. 

At least one vitamin E deficiency sign is known to occur only when a certain class of polyunsaturated fatty acids is furnished in the diet. For instance, encephalomalacia in chicks appears when the diet contains linoleic or arachidonic acid, but not when the diet is fat free or contains linolenic acid. It is possible that encephalomalacia is due to the lack of an antioxidant effect, but attempts to demonstrate autoxidation products in the affected tissue have not been successful. 

In 1930, linoleic cis, cis-9,12-octadecadienoic) acid was shown to be effective in preventing the development of certain conditions in rats given diets almost devoid of fat. These animals showed a scaly appearance of the skin and suboptimal performance in growth, reproduction and lactation eventually they died as a result of the deficient diet. More recent work has demonstrated a wide range of symptoms in a variety of animals, including some in human beings under certain circumstances (Table 3.3). 

However the activation of the A6 desaturation is shown later on. At 15 days it is very important. The apparent Km and Vm of the enz)mie are modified. This activation recovers the double bond index saturated acid ratio to 2.2 and is correlative to an increase of the triacylglycerol phosphatidyl choline ratio of the microsomes. Undoubtedly it is not correlative to the modification of the fatty acid composition of the membrane. Besides Ayala and Brenner have shown that the effect is not due to substrate deprivation (linoleate or a-linolenate) since rats fed on diets containing fish oil during 4 or 6 weeks have even lower A6 desaturation activity in liver microsomes than animals fed on sunflower seed oil compared to rats fed on EFA free diets (Table 2), Therefore the increase of the A6 desaturase activity in EFA deficiency is a physiological response of the cell to maintain the unsaturated/saturated acid ratio and fluidity of the membrane. 

Table 2. Comparative effect of EFA deficient diets supplemented with fish oil, sunflower seed oil and methyl palmitate in the A6 desaturation (%) of linoleic and a-linolenic acid bv rat liver microsomes >...

Pure fatty acid hydroperoxides are very toxic to experimental animals when administered intravenously (i.v.) but not oraUy (Horgan et al., 1957 Olcott and Dolev, 1963 Findlay et al., 1970). Cortesi and Privett (1972) have shown that the 24-h lethal i.v. dose of a high purity preparation of methyl linoleate hydroperoxides in adult male rats was approximately 0.07 mmol/100 g body weight, and that the major effect of injected linoleate hydroperoxides was on the lungs. Also, vitamin E deficiency symptoms such as encephalomalacia in chicks (Nishida et al., 1960), and creatinuria and erythrocyte hemolysis in rabbits (Kokatnur et al., 1966) have been observed in animals infused with methyl linoleate hydroperoxides. 

The first proof that fats comprise a necessary component in the diet was adduced in 1926 by Evans and Burr. Shortly thereafter, McAmis et al. (1929) also reported that rats grew better on fat-containing diets than on regimens deficient in this foodstuff in fact, the latter workers reported deficiency symptoms in rats which received the fat-free diets. It remained for Burr and Burr (1929) to demonstrate in a clear-cut manner that the beneficial effect of fat on growth was due to the fact that it prevented a dietary disease. This deficiency condition was not to be ascribed to the lack of vitamins A and D, but rather to the absence of components present in the saponifiable fraction. The latter active compounds were shown to be polyunsaturated fatty acids, which are usually referred to as essential fatty adds (EFA). The fat eficiency symptoms produced by a fat-free diet were found to disappear in a dramatic fashion when certain unsaturated fats, or linoleic, linolenic, or arachidonic acids, were fed (Burr and Burr, 1930). Earlier reviews of the nutritional significance of the EFA included that of Burr (1942), and of... 

Proof that the deficiency produced by the inclusion of mineral oil in the diet is a fat deficiency was based not only upon the typical symptoms which developed but also upon the fact that the inclusion of 50 mg. of linoleate per day in the diet prevented them. Moreover, there was an increased excretion of fatty acids in the feces of mineral oil-fed rats in addition, the fecal fatty acids were found to have an increased iodine value after the ingestion of mineral oil. However, it is believed that this effect cannot be ascribed solely to the solvent action of the hydrocarbon on EFA, since the deficiency symptoms were prevented by the administration of linoleate either orally or intraperitoneally. 

Known relations with other diseases (a number of them sometimes called civilization diseases ) are present, for instance, via the essential fatty acids, a deficiency of which has been described also in idiopathic hypercalcemia in infants (Sinclair, 1956, 1957, 1958a Frazer 1956 Bongiovanni et al., 1957). These authors also reported in this connection a greater susceptibility to vitamin D intoxication. A deficiency of essential fatty acids, and good responses from their administration, have been noted by Hansen (1933,1957) and Hansen et al. (1947) in infant eczema. Treatment of exudative diathesis in children of a somewhat older age by avoiding animal fats is often successful, if properly done. That the functions and effects of the (essential) unsaturated fatty acids are not completely the same is demonstrated clearly by the fact that linolenate cannot cure the dermal symptoms in rats on a fat-deficient diet, whereas linoleate does so readily. Other mp-toms can be relieved by both. 

It may be that the defect in the plasma membrane phospholipids presumably produced by the EFA deficiency is similar to an abnormality produced by the displacement of linoleic and arachidonic acids by the excess phytanic acid in Refsum s syndrome and that there is a special relationship between the plasma membrane and cell division. The normal rate of cell production in dominant ichthyosis that we have found is in agreement with previous workers and the scaliness in these patients is an optical and sensory effect from the abnormal type of desquamation in these patients rather than an increase in scale production. We believe that the hyperkeratotic type of lamellar ichthyosis is special in that there is a normal or low rate of cell production in contradistinction to the erythrodermatous types. 

---