USES OF ESSENTIAL FATTY ACIDS
Edited by David F.
®1982 Eden Press
ESSENTIAL FATTY ACIDS:
This book is out of
The following is taken from Chapter 1.
Clinical Uses Of Essential Fatty Acids
David F. Horrobin
(PUFAs) are fatty acids which have two or more double bonds linking
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
rich in PUFAs. Coconut oil and palm oil largely consist of saturated
while olive oil contains large amounts of the mono-unsaturated oleic
WHAT ARE ESSENTIAL
are dietary factors which were discovered at the University of
by George and Mildred Burr in 1929. Like vitamins EFAs cannot be made
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
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
omega end of the molecule. The n6 series seems to be considerably more
important but the n3 series are now beginning to be intensively
with particular reference to their roles in cardiovascular function and
in the brain.
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
of the fatty acids in the sequence are by no means fully known. It is
that unless cis-linoleic acid can be converted to gamma-linolenic acid
(GLA), it has no biological activity as an EFA (5)
The two series of
n3 and the n6 series are not interchange-able in animals. However the
which metabolize the n6 and the n3 series seem to be identical. There
considerable species differences between EFA metabolism which will be
in later sections. In particular, delta-5-desaturase activity is high
rats and mice but low in humans and guinea pigs (13).
EFAs are important
quite different reasons. First they are constituents of all membranes
all tissues of the body. They play a vital role in determining the
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
of a group of highly reactive, short-lived molecules, the
(PGs) and leukotrienes (LTs). These substances serve a wide variety of
functions and each cell type produces a specific pattern of PGs and
There are over fifty types of PGs and LTs and related molecules known
new ones are discovered every year. There are powerful mechanisms
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
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
incredible variety of effects, some highly desirable and some harmful.
Three of the EFAs can act as precursors for PGs, dihomogammalinolenic
(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
leads to are either neutral or, like PGE1, very desirable in their
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,
a very mixed bag of substances. Unlike DGLA it can give rise to LTs
are very pro-inflammatory. Some of the PGs it leads to such as PG12
have desirable effects such as inhibition of platelet aggregation and
Others, such as thromboxane A2 (TXA2, a substance closely related to
and PGF2a have largely undesirable effects such as promo-tion of
thrombosis and inflammation. The PGs and thromboxanes are formed from
by a cyclo-oxygenase enzyme system while the leukotrienes are formed by
a lipoxygenase enzyme system (figure 2) (7, 8).
are found in abundance wherever any form of inflammation is taking
In order for these products to be formed, AA must first be released
membrane stores and converted to a free form. The free AA can then be
either to leukotrienes and related compounds or to prostaglandins and
compounds. Aspirin and other non-steroidal anti-inflammatory drugs
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
drugs may leave more free AA to be converted to LTs and so provoke an
This appears to be the mechanism behind aspirin-induced asthma.
are much more potent anti-inflammatories than the aspirin-like
because they block the release of arachidonic acid and so inhibit the
of both PGs and LTs. PGE1 has a steroid-like action in blocking AA
( 9, 10). At present less is known about selective inhibitors of the
pathway. Vitamin E is one such inhibitor (145). Another is a hydroxy
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
between DGLA and AA, with adequate amounts of DGLA and its products
required to control inflammation (10).
Much less is known
of EPA. On the whole they seem to be much less potent than those of
or AA and to be either neutral or positive in their effects. One
action of EPA is to compete with AA and so to prevent the conversion of
AA to inflammatory metabolites (12).
EFA METABOLISM IN
In rats the
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
are so extensively used for experiments on EFAs and PGs because EFA
in humans is quite different. In adult humans DGLA is converted to AA
very slowly if at all (13). Guinea pigs are similar to humans in this
and it may be significant that the immune and inflammatory systems of
guinea pig tend to be rather similar to those in humans.
Because of the low
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
to DGLA, comes mainly from vegetable sources although organ meats
some. Arachidonic acid comes mainly from meat and some seafoods,
being a particularly rich source. There is also arachidonic acid in
sea-weeds. On the whole, however, the diets of vegetarians are likely
contain primarily 1 series PG precursors while those of meat eaters
both. Some of the health differences between meat eaters and
could be related to this.
ACUTE EFA DEFICIENCY
Much less is known
and what we do know has come from two unusual circumstances. In the
when much research was being done on artificial milk preparations for
some formula-tions were made in which EFA levels were far too low. The
most striking observations in these infants were dry, scaly skin,
rashes, irritability and a substantial increase in calorie intake (16,
17). The infants fed these formulae had much larger appetites than
taking a normal EFA diet. Addition of EFAs to the formulae reduced
and caused rapid clearing of the skin.
In the 1970s, when
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
resembling psoriasis or eczema, failure of wound healing and
being prominent (18-21).
No specific work has
done on chronic EFA deficiency in either animals or humans. It is
not known what the long term effects of a partial EFA deficiency might
be in either animals or humans.
However there are
ways of investigating what an essential nutrient does. The first is to
deprive individuals of that nutrient and to watch what happens. The
is to administer an excess of the nutrient. If on giving an apparent
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
Doctors and authoritative national and international committees have
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
149). Curiously, EFAs are the only nutrients which the medical
consistently advises their patients to take in mega-doses. These
have been found to have desirable effects in a variety of conditions,
cardiovascular problems, diabetes, breast and menstrual cycle problems
and multiple sclerosis.
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
the delta-6-desaturase enzyme which is required for the metabolism of
cis-linoleic acid and alpha-linolenic acid, is lost with aging: It
in the gonads first and later in the rest of the body. Loss of this
means that aging animals inevitably become functionally deficient in
Even though they may be taking normal amounts of linoleic and
acids in the diet, they cannot make use of these as functional EFAs.
As yet only a few
in humans have addressed themselves to this problem (25-27). However
strongly suggest that the enzyme is lost or only partly functional in
humans. Administration of linoleic acid to older humans usually
little change in DGLA. However administration of small amounts of
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
that humans, as they become older, will also become functionally EFA
because of inability to metabolize the usual dietary sources of EFAs.
THE IMPORTANCE OF
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
to 18:4 n3. For over 20 years Brenner has conducted a systematic
of the behaviour of this enzyme. His findings and those of other groups
are as follows (22, 31, 32):
inhibit the activity of the enzyme.
acids formed by the processing of vegetable oils inhibit the enzyme.
animals the activity of the enzyme is low (28).
the enzyme (29).
to loss of enzyme activity.
inhibits the enzyme, an effect mediated by beta-receptors since
it can be abolished by beta blockade. This is a neglected potential
action of beta-blockers in cardio-vascular disease.
inhibits the enzyme, but a restricted calorie intake may increase
enzyme activity three fold (150) .
inhibit the enzyme.
9. A very
protein diet inhibits the enzyme whereas a very high protein
diet activates it.
10. Administration of
to normal animals inhibits the enzyme.
11. Oncogenic viruses
ionizing radiation inhibit the enzyme (30).
It is thus apparent
large number of agents which are known to have profound effects on
(e.g. alcohol, diabetes, calorie restriction, catecholamines,
glucose) also have major effects on the D6D and so regulate the
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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