114 Introduction to Human Nutrition
unsaturates led to defi ciency of n-3 polyunsaturates,
characterized by delayed and impaired neuronal
development and impaired vision. These symptoms
have been traced in many species to the inadequate
accumulation of docosahexaenoate in the brain and
eye. Hence, the main function of n-3 polyunsaturates
appears to hinge on synthesis of docosahexaenoate.
In contrast, the function of n-6 polyunsaturates
involves independent roles of at least linoleate and
arachidonate.
Human cases of defi ciency of PUFAs, usually
involve a clinical disorder, often involving weight loss,
trauma such as surgery, or a disease requiring paren-
teral nutrition. However, reports of these cases are
uncommon and describe dissimilar characteristics,
leading one to question whether the same defi ciency
exists. Recent investigations into the amount of PUFA
in the whole body and the rate at which they can be
oxidized suggest that traumatic or disease-related
processes leading to weight loss affect metabolism of
polyunsaturates more severely than simple dietary
defi ciency in a weight-stable, healthy individual. For
example, defi ciency of linoleate has been long sus-
pected but diffi cult to demonstrate in cystic fi brosis.
Despite poor fat digestion, intake levels of linoleate
may not be inadequate but its β-oxidation could well
be abnormally high owing to the chronic infectious
challenge.
Clinical importance of polyunsaturates
Infant brain and visual development is dependent on
adequate accumulation of docosahexaenoate. The
1990s saw intense clinical and experimental assess-
ment of the role of docosahexaenoate in early brain
development and a widespread concern that many
infant formulae do not yet contain docosahexaenoate.
Several clinical studies and extensive use of formulae
containing docosahexaenoate and arachidonate have
shown that they are safe. Many but not all such studies
show an improvement in visual and cognitive scores
compared with matched formulae containing no
docosahexaenoate or arachidonate. The infant brain
and body as a whole clearly acquire less docosahexae-
noate when only α-linolenate is given. As a whole,
these data suggest that docosahexaenoate is a condi-
tionally indispensable fatty acid.
Aside from questionable defi ciency of polyunsatu-
rates in cystic fi brosis (see above), one of the most
graphic examples of their defi ciency being caused by
an inherited disease is Zellweger’s syndrome. This
condition causes severe mental retardation and early
death. It is a disorder of peroxisomal biogenesis and
one outcome is markedly impaired synthesis of doco-
sahexaenoate. Dietary supplementation with docosa-
hexaenoate appears to partially restore neurological
development.
Epidemiological evidence shows that chronic
degenerative diseases of affl uence are directly associ-
ated with the defi ciency of n-3 PUFAs. Indeed, coun-
tries with relatively high rates of these diseases usually
have an adequate to perhaps unnecessarily higher
intake of linoleate. High intakes of linoleate have been
implicated in death from coronary artery disease and
several types of cancer because these diseases are asso-
ciated with low intakes of n-3 polyunsaturates. Mental
illnesses such as schizophrenia may also be associated
with low intake of n-3 polyunsaturates and respond to
supplements of n-3 polyunsaturates. A more balanced
ratio of intake of n-6 and n-3 polyunsaturates might
achieve a reduction in the rate of these degenerative
diseases but has not yet been widely investigated.
Diets in Paleolithic times contained no processed
food and probably balanced amounts of n-3 to n-6
polyunsaturates and a lower level of saturates. Such
diets would be predicted to lead to a lower incidence
of degenerative disease. Since the brain has a very
high energy requirement, it has also been speculated
that human brain evolution beyond that of other pri-
mates was dependent on a reliable and rich source of
dietary energy and a direct source of long-chain poly-
unsaturates, particularly docosahexaenoate.6.10 Cholesterol synthesis and regulation
Cholesterol and the brain
Mammalian brain function is dependent on special-
ized membranes designed for signal transmission.
Greater cognitive sophistication in humans appears
to depend on a much greater number of connections
and, consequently, greater potential for signal pro-
cessing. Like the membrane lipids of most other
mammalian organs, brain lipids contain a relatively
high proportion of cholesterol, which increases from
about 40% of the lipid content in neonates to nearly
50% in adults.
Unlike other organs, the mammalian brain is prob-
ably unique in being unable to acquire appreciable