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Overview of Essential Fatty Acids

CLINICAL USES OF ESSENTIAL FATTY ACIDS
Edited by David F. Horrobin
1982 Eden Press Inc.
ESSENTIAL FATTY ACIDS: A REVIEW
This book is out of print.  The following is taken from Chapter 1.

Clinical Uses Of Essential Fatty Acids

David F. Horrobin
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WHAT ARE POLYUNSATURATES?

Polyunsaturated fatty acids (PUFAs) are fatty acids which have two or more double bonds linking carbon atoms in the molecule (1). On the whole they tend to be found in liquid form, unless they are complexed with other fats. Not all liquid fats are rich in PUFAs. Coconut oil and palm oil largely consist of saturated fats while olive oil contains large amounts of the mono-unsaturated oleic acid.

WHAT ARE ESSENTIAL FATTY ACIDS?

Essential fatty acids (EFAs) are dietary factors which were discovered at the University of Minnesota by George and Mildred Burr in 1929. Like vitamins EFAs cannot be made by the body but must be taken in with the food (1, 2). All EFAs are PUFAs, but most PUFAs are not EFAs (3, 4). In order to act as an EFA, highly specific chemical structures are required. There are two series of EFAs, the n6 derived from cis-linoleic acid, and the n3 derived from alpha-linolenic acid. The numbers indicate the position of the first double bond from the omega end of the molecule. The n6 series seems to be considerably more important but the n3 series are now beginning to be intensively investigated with particular reference to their roles in cardiovascular function and in the brain.

Like certain vitamins, cis-linoleic acid and alpha-linolenic acid have no biological activity of their own, apart from being oxidized to provide energy. If they are to function as EFAs, they require specific biochemical transformation within the body. The reaction sequences are shown in figure 1. The exact functions of each of the fatty acids in the sequence are by no means fully known. It is known that unless cis-linoleic acid can be converted to gamma-linolenic acid (GLA), it has no biological activity as an EFA (5)  

Figure 1


 

The two series of EFAs, the n3 and the n6 series are not interchange-able in animals. However the enzymes which metabolize the n6 and the n3 series seem to be identical. There are considerable species differences between EFA metabolism which will be discussed in later sections. In particular, delta-5-desaturase activity is high in rats and mice but low in humans and guinea pigs (13).

EFAs are important for two quite different reasons. First they are constituents of all membranes in all tissues of the body. They play a vital role in determining the biological properties of all these membranes. It is therefore not surprising that EFA deficiency leads to profound disturbances in all tissues (1, 2).

Second, EFAs are the precursors of a group of highly reactive, short-lived molecules, the prostaglandins (PGs) and leukotrienes (LTs). These substances serve a wide variety of functions and each cell type produces a specific pattern of PGs and LTs. There are over fifty types of PGs and LTs and related molecules known and new ones are discovered every year. There are powerful mechanisms within cells for degrading PGs and LTs and almost all PGs are removed from the blood during a single passage through the lungs. The main actions of these substances therefore seem to be as local messengers which regulate the activity of the tissues in which they are produced (6, 7).

The PGs and LTs have an almost incredible variety of effects, some highly desirable and some harmful. Three of the EFAs can act as precursors for PGs, dihomogammalinolenic acid (DGLA) and arachidonic acid (AA) of the n6 series and eicosapentaenoic acid (EPA) of the n3 series. DGLA cannot give rise to LTs and the PGs it leads to are either neutral or, like PGE1, very desirable in their actions. PGE 1 is an activator of cyclic AMP formation, an inhibitor of platelet aggregation, a vasodilator, an inhibitor of inflammatory reactions and an activator of T lymphocyte function (7).

AA, in contrast, produces a very mixed bag of substances. Unlike DGLA it can give rise to LTs which are very pro-inflammatory. Some of the PGs it leads to such as PG12 (prostacyclin) have desirable effects such as inhibition of platelet aggregation and vasodilatation. Others, such as thromboxane A2 (TXA2, a substance closely related to PGs) and PGF2a have largely undesirable effects such as promo-tion of vasospasm, thrombosis and inflammation. The PGs and thromboxanes are formed from AA by a cyclo-oxygenase enzyme system while the leukotrienes are formed by a lipoxygenase enzyme system (figure 2) (7, 8).

Figure 2

Arachidonic acid products are found in abundance wherever any form of inflammation is taking place. In order for these products to be formed, AA must first be released from membrane stores and converted to a free form. The free AA can then be converted either to leukotrienes and related compounds or to prostaglandins and related compounds. Aspirin and other non-steroidal anti-inflammatory drugs inhibit inflammation by blocking the cyclo-oxygenase only. If LTs are important in a reaction, as they seem to be in asthma for example, aspirin and related drugs may leave more free AA to be converted to LTs and so provoke an exacerbation. This appears to be the mechanism behind aspirin-induced asthma. Steroids are much more potent anti-inflammatories than the aspirin-like compounds because they block the release of arachidonic acid and so inhibit the formation of both PGs and LTs. PGE1 has a steroid-like action in blocking AA mobilisation ( 9, 10). At present less is known about selective inhibitors of the lipoxygenase pathway. Vitamin E is one such inhibitor (145). Another is a hydroxy acid which can be formed from DGLA (11). DGLA derivatives therefore inhibit the formation of inflammatory substances from AA in two quite distinct ways. This has led to the proposal that there is a negative feedback balance between DGLA and AA, with adequate amounts of DGLA and its products being required to control inflammation (10).

Much less is known about derivatives of EPA. On the whole they seem to be much less potent than those of DGLA or AA and to be either neutral or positive in their effects. One important action of EPA is to compete with AA and so to prevent the conversion of AA to inflammatory metabolites (12).

EFA METABOLISM IN HUMANS

In rats the delta-5-desaturase which converts DGLA to AA is highly active and so linoleic acid in the diet is rapidly converted to AA (13). It is perhaps unfortunate that rats are so extensively used for experiments on EFAs and PGs because EFA metabolism in humans is quite different. In adult humans DGLA is converted to AA only very slowly if at all (13). Guinea pigs are similar to humans in this respect and it may be significant that the immune and inflammatory systems of the guinea pig tend to be rather similar to those in humans.

Because of the low activity of the delta-5-desaturase, in humans the balance between 1 and 2 series PGs may be readily influenced by the diet. Linoleic acid, which gives rise to DGLA, comes mainly from vegetable sources although organ meats contain some. Arachidonic acid comes mainly from meat and some seafoods, shrimps being a particularly rich source. There is also arachidonic acid in some sea-weeds. On the whole, however, the diets of vegetarians are likely to contain primarily 1 series PG precursors while those of meat eaters contain both. Some of the health differences between meat eaters and vegetarians could be related to this.

ACUTE EFA DEFICIENCY IN HUMANS

Much less is known about this and what we do know has come from two unusual circumstances. In the 1950s, when much research was being done on artificial milk preparations for infants, some formula-tions were made in which EFA levels were far too low. The most striking observations in these infants were dry, scaly skin, eczema-like rashes, irritability and a substantial increase in calorie intake (16, 17). The infants fed these formulae had much larger appetites than contemporaries taking a normal EFA diet. Addition of EFAs to the formulae reduced appetite and caused rapid clearing of the skin.

In the 1970s, when fluids for total parenteral nutrition were being developed, the American Food and Drug Administration would not allow EFAs to be included. The result was a series of reports of acute EFA deficiency in adults, with skin rashes resembling psoriasis or eczema, failure of wound healing and irritability being prominent (18-21).

CHRONIC EFA DEFICIENCY

No specific work has been done on chronic EFA deficiency in either animals or humans. It is therefore not known what the long term effects of a partial EFA deficiency might be in either animals or humans.

However there are two classical ways of investigating what an essential nutrient does. The first is to deprive individuals of that nutrient and to watch what happens. The second is to administer an excess of the nutrient. If on giving an apparent excess of a nutrient, certain manifestations of disease disappear, then it is legitimate to conclude that those manifestations may have resulted from long term partial deficiency. Over the past 25 years, this second type of study has repeatedly been carried out using PUFAs as sources of EFAs. Doctors and authoritative national and international committees have repeatedly urged patients to take 10-15% of their total calorie intake in the form of EFAs. This is in contrast to the 1% of total calorie intake which is adequate to support normal growth and development of young animals (148, 149). Curiously, EFAs are the only nutrients which the medical profession consistently advises their patients to take in mega-doses. These mega-doses have been found to have desirable effects in a variety of conditions, notably cardiovascular problems, diabetes, breast and menstrual cycle problems and multiple sclerosis.

Another important development in relation to chronic EFA deficiency arises from the work of Brenner's group on aging and EFA metabolism (22-24). They have shown that in animals, the delta-6-desaturase enzyme which is required for the metabolism of both cis-linoleic acid and alpha-linolenic acid, is lost with aging: It disappears in the gonads first and later in the rest of the body. Loss of this enzyme means that aging animals inevitably become functionally deficient in EFAs. Even though they may be taking normal amounts of linoleic and alpha-linolenic acids in the diet, they cannot make use of these as functional EFAs.

As yet only a few studies in humans have addressed themselves to this problem (25-27). However these strongly suggest that the enzyme is lost or only partly functional in older humans. Administration of linoleic acid to older humans usually produces little change in DGLA. However administration of small amounts of gamma-linolenic acid, which by-passes the enzymes, leads to a 3-8 fold rise in DGLA in plasma and platelets (25, 26). If these findings are con-firmed, they mean that humans, as they become older, will also become functionally EFA deficient because of inability to metabolize the usual dietary sources of EFAs.

THE IMPORTANCE OF THE DELTA-6-DESATURASE

The delta-6-desaturase (D6D) enzyme is absolutely vital to an under-standing of the EFAs since it is a gatekeeper for both the n6 and the n3 series (figure 1). It converts cis-linoleic acid to gamma-linolenic acid (GLA), and alpha-linolenic acid to 18:4 n3. For over 20 years Brenner has conducted a systematic investigation of the behaviour of this enzyme. His findings and those of other groups are as follows (22, 31, 32):

1.   Saturated fats inhibit the activity of the enzyme.
2.   Trans fatty acids formed by the processing of vegetable oils inhibit the enzyme.
3.   In diabetic animals the activity of the enzyme is low (28).
4.   Alcohol inhibits the enzyme (29).
5.   Aging leads to loss of enzyme activity.
6.   Adrenaline inhibits the enzyme, an effect mediated by beta-receptors since 
      it can be abolished by beta blockade. This is a neglected potential site of 
      action of beta-blockers in cardio-vascular disease.
7.   Starvation inhibits the enzyme, but a restricted calorie intake may increase
      enzyme activity three fold (150) .
8.   Glucocorticoids inhibit the enzyme.
9.   A very low protein diet inhibits the enzyme whereas a very high protein 
      diet activates it.
10. Administration of glucose to normal animals inhibits the enzyme.
11. Oncogenic viruses and ionizing radiation inhibit the enzyme (30).

It is thus apparent that a large number of agents which are known to have profound effects on health (e.g. alcohol, diabetes, calorie restriction, catecholamines, beta-blockers, glucose) also have major effects on the D6D and so regulate the availability of EFAs to the body. The effects of these agents on the D6D are rarely considered when their sites of action are being explored.

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