Efficiency of conversion of a-linolenic acid to long chain n-3 fatty
acids in man
J. Thomas Brenna
a-Linolenic acid (18:3n-3) is the major n-3 (o3) fatty acid in the
human diet. It is derived mainly from terrestrial plant
consumption and it has long been thought that its major
biochemical role is as the principal precursor for long chain
polyunsaturated fatty acids, of which eicosapentaenoic
(20:5n-3) and docosahexaenoic acid (22:6n-3) are the most
prevalent. For infants, n-3 long chain polyunsaturated fatty acids
are required for rapid growth of neural tissue in the perinatal
period and a nutritional supply is particularly important for
development of premature infants. For adults, n-3 long chain
polyunsaturated fatty acid supplementation is implicated in
improving a wide range of clinical pathologies involving cardiac,
kidney, and neural tissues. Studies generally agree that whole
body conversion of 18:3n-3 to 22:6n-3 is below 5% in humans,
and depends on the concentration of n-6 fatty acids and long
chain polyunsaturated fatty acids in the diet. Complete oxidation
of dietary 18:3n-3 to CO2 accounts for about 25% of 18:3n-3 in
the first 24 h, reaching 60% by 7 days. Much of the remaining
18:3n-3 serves as a source of acetate for synthesis of saturates
and monounsaturates, with very little stored as 18:3n-3. In term
and preterm infants, studies show wide variability in the plasma
kinetics of 13C n-3 long chain polyunsaturated fatty acids after
13
C-18:3n-3 dosing, suggesting wide variability among human
infants in the development of biosynthetic capability to convert
18:3n-3 to 22:6n3. Tracer studies show that humans of all ages
can perform the conversion of 18:3n-3 to 22:6n3. Further
studies are required to establish quantitatively the partitioning of
dietary 18:3n-3 among metabolic pathways and the influence of
other dietary components and of physiological states on these
processes. Curr Opin Clin Nutr Metab Care 5:127±132. # 2002 Lippincott
Williams & Wilkins.
Division of Nutritional Sciences, Savage Hall, Cornell University, Ithaca, New York,
USA
Correspondence to J.T. Brenna, Division of Nutritional Sciences, Savage Hall, Cornell
University, Ithaca, NY 14853, USA
Tel: +1 607 255 9182; fax: +1 607 255 1033; e-mail: jtb4@cornell.edu
Current Opinion in Clinical Nutrition and Metabolic Care 2002, 5:127±132
Abbreviations
18:3n-3* isotopically-labeled 18:3n-3
20:5n-3* isotopically-labeled 20:5n-3
22:5n-3* isotopically-labeled 22:5n-3
22:6n-3* isotopically-labeled 22:6n-3
AUC area under the curve
LCP long chain polyunsaturates, with 20 or more carbons
PUFA polyunsaturated fatty acids of all chain lengths
# 2002 Lippincott Williams & Wilkins
1363-1950
Introduction
a-Linolenic acid (18:3n-3) is regarded as the parent
compound of the n-3 polyunsaturated fatty acid (PUFA)
series because it is the most common n-3 PUFA in
terrestrial diets and serves as the precursor for all n-3
long chain polyunsaturates (LCP) found in mammals. It
is a structural analog of linoleic acid (18:2n-6), the most
prominent n-6 PUFA in the western diet. 18:2n-6 serves
as precursor for the long chain PUFA arachidonic acid
(20:4n-6), a substrate for cyclooxygenases, lipoxygenases,
and P450 enzymes. n-3 LCP analogous to all n-6 LCP
are found in mammals, and they often undergo
equivalent biochemical transformations as n-6 LCP, for
example the conversion of eicosapentaenoic acid (20:5n-3)
into eicosanoids by enzymes that act on 20:4n-6. Because
some metabolic properties have been reported for 18:2n-6
but not 18:3n-3, this review will occasionally draw on
18:2n-6 data.
18:3n-3 concentrations in plasma and tissues tend to be
lower than 18:2n-6 concentrations even when 18:3n-3 is
rich in the diet, and 18:3n-3 storage as triglycerides in
adipose is also relatively low. Dietary 18:3n-3 is
metabolically transformed in three well-known ways: (1)
conversion to n-3 LCP, (2) b-oxidation, with shunting of
the resulting acetate to complete oxidation to CO2, or (3)
b-oxidation and use of acetate for biosynthesis. A fourth
process of signi®cance may exist: 46% of radioactivity
associated with a [14C]-18:3n-3 dose was found 48 h later
in skin and fur lipids of guinea pigs, while less than 0.1%
was found in brain [1 . .]. This report indicates that a
substantial amount of 18:3n-3 is transported to the skin,
however the ®nding is recent and awaits considerable
work to establish its signi®cance in humans. The relative
partitioning among these routes determines the ef®-
ciency of conversion of 18:3n-3 to LCP, and this in turn
depends critically on physiological and nutritional state.
We ®rst outline the biochemistry of 18:3n-3 conversion
to LCP, then we evaluate clinically relevant measure-
ments of conversion, and ®nally we examine alternative
metabolic fates of 18:3n-3 as they relate to factors
affecting conversion ef®ciency.
Biosynthesis of n-3 long chain
polyunsaturates
The pathways for synthesis of n-3 LCP from 18:3n-3
remain a subject of active research. Until 1991, the
pathway was assumed to proceed in the endoplasmic
127
128 Lipid metabolism
reticulum via a series of alternating desaturations and
elongations through n-3 intermediates as follows:
18:3?18:4?20:4?20:5?22:5?22:6 [2]. Voss et al. [3]
proposed that the last step of this pathway, a delta-4
desaturase, does not exist in rat liver, and by implication
in humans, and they postulated an alternative where 18:3
is transformed into 24:6n-3 in the endoplasmic reticulum,
then 24:6n-3 is transported to peroxisomes for a single
round of b-oxidation in the last step, as follows:
18:3?18:4?20:4?20:5?22:5?24:5?24:6?22:6; sup-
port for this pathway has been summarized [4 . .]. This
view has gained wide acceptance, based primarily on
kinetic data, though it has been challenged with the
suggestion that delta-4 desaturation mediates the last
step [5 .]. A delta-4 desaturase which converts 22:5n-3 to
22:6n-3 has been cloned from a eukaryotic single cell
marine organism rich in 22:6n-3 [6 .]; as of this writing, no
analogous mammalian enzyme has been reported. For
the present clinical discussion, it is suf®cient to consider
the (22:5?22:6) step in the pathway a net delta-4
desaturation since the C24 LCP are present at very
low levels and have no known function per se, except
possibly as intermediates.
The major n-3 LCP appearing in human tissues are
primarily limited to 20:5n-3, 22:5n-3, and 22:6n-3.
Intermediates or longer chain derivatives can be found
only at trace levels in healthy volunteers. Studies of
18:3n-3 conversion in humans fall into two classes: (1)
dietary studies, in which experimental diets are con-
sumed over a speci®ed period and components of blood
(e.g. plasma or erythrocytes) or other accessible tissue
such as cheek epithelial cells are analysed for changes in
fatty acid composition; (2) tracer studies, where stable
isotopes are administered and tracer concentrations
determined. Tracer studies in humans excel at determin-
ing if a particular biochemical transformation occurs, but
extrapolations of analyses of blood components (e.g.
plasma) to whole body or even tissue-level conversion are
tenuous. Human dietary studies excel at probing overall
shifts in PUFA concentrations due to particular diets or
altered physiological states and provide limited informa-
tion about mechanism; again, extrapolation is dif®cult.
Reliable measurement of tissue and tissue level accretion
or conversion is best accomplished with appropriate
experimental animals using dietary or tracer studies.
Conversion measurements
In general, the clinically-relevant literature addresses
18:3n-3 metabolism in the perinatal period in the context
of requirements for growth of neural tissues, or in adults in
the context of chronic disease. We consider each in turn.
Perinatal metabolism
Perinatal studies of the conversion ef®ciency of 18:3n-3
to 22:6n-3 are motivated by several factors, most
importantly (1) the presence of 22:6n-3 and other n-3
LCP in breastmilk [7] but their absence in many infant
formulas; (2) tissues such as retina and brain that are rich
in n-3 LCP; (3) the emergence of prematurity-related
de®ciencies, particularly in neural function, as an
important health outcome, and the related observation
that n-3 LCP begin to accumulate in large amounts in
neural tissue in the last trimester of pregnancy [8].
Signi®cant desaturase activities have been detected in
the livers of aborted human fetuses as early as 17 weeks
of gestation, indicating that at least some of the
molecular machinery for conversion is present [9].
Furthermore, direct administration of labeled 18:3n-3
to baboon fetuses demonstrates that the conversion is
actively performed in primates in vivo [10 . .]. The latter
data show that brain accumulation of 22:6n-3 is about
4.6% of dose compared with about 0.57% of an 18:3n-3
dose found as 22:6n-3. Stable isotope tracer studies
established qualitatively that premature infants can
perform the conversion from 18:3n-3 to 22:6n-3, as well
as 18:2n-6 to 20:4n-6 [11±13]. For practical and ethical
reasons, these studies analyse only limited amounts of
plasma, which cannot be used to infer absolute conver-
sion ef®ciencies. Plasma tracer and precursor-product
data support the idea that preterm infants on average
have at least as active conversion of 18:3n-3 to 22:6n-3 as
term infants. Integrated area-under-the-curve (AUC)
estimates for plasma fatty acids are greatest for preterm
infants and lowest for term and intrauterine growth
retarded infants for the 18:3?22:6 conversion [14 . .].
Data supporting increased ef®ciency for preterms are
consistent with previous results, including measure-
ments showing that fetal baboon brain accretion of
22:6n-3 derived from 18:3n-3 is more than twice as
ef®cient as for term neonates [10 . .,15]. This extensive
dataset, however, also shows that conversion ef®ciency
among infants is highly variable, with standard devia-
tions approximately equal to the mean values, suggest-
ing that some infants at the low end may be vulnerable
to poor LCP supply. Whole body estimates of 18:3n-3
conversion cannot be extracted from plasma data.
Adult metabolism
n-3 LCP administration to adults is known to exert a
positive in¯uence on a variety of clinical conditions as
disparate as the prevention of cardiac arrhythmias [16 .],
psychiatric disorders [17], and nephropathy [18 .], prob-
ably by more than one mechanism. An excellent
summary of active PUFA health-related research has
appeared as a journal supplement [19 . .].
Several stable isotope tracer studies have shown healthy
adults to synthesize 22:6n-3 from 18:3n-3 [20±22].
Absolute AUC estimates were made for adult males
with retinitis pigmentosa or normal controls. Variability
of peak 18:3* and 22:6* over a factor of ®ve was
 Conversion of a-linolenic acid to long chain n-3 fatty acids Brenna 129
observed in kinetics; AUC estimates for the transforma-
tion 18:3n3?22:6n-3 were estimated at 5%, over a 504 h
(21-day) period. This is the highest estimated conversion
ef®ciency and may re¯ect the extended observation
period reported to date [23 . .]. Using an isotopically-
labeled 18:3n-3 (18:3n-3*) dose, isotopically-labeled
20:5n-3 (20:5n-3*) and isotopically-labeled 22:6n-3
(22:6n-3*) AUCs were 34 and 20%, respectively, of the
total AUC for n-3 LCP for adults on low 22:6n-3 diets, in
a 3-day study [24]. Overall conversion was reportedly
attenuated when 6 g 22:6n-3 was included in the diet.
AUC estimates, though routine, do not account for
turnover within pools and therefore provide rough
estimates of relative abundances. Turnover was taken
into account in a recent comprehensive phenomenolo-
gical approach to 18:3n-3 to n-3 LCP conversion using
high sensitivity mass spectrometric analysis of penta-
deuterated tracers [25 . .]. Eight healthy adults consumed
a controlled diet with olive oil, beef and butter, food
items which do not contain signi®cant amounts of n-3
LCP as the major fat sources. An isotopic tracer of
18:3n-3 was administered orally and the plasma kinetics
of 18:3n-3*, 20:5n-3*, 22:5n-3*, and 22:6n-3* were
determined. From these data, half-lives and kinetic
constants for each fatty acid were determined using a
compartmental model. The model uses pools for each of
the four major n-3 PUFA in plasma connected by
kinetic constants for transfer of label from intestine
into plasma and within plasma along the pathway
18:3?20:5?22:5?22:6, and with kinetic constants for
losses from each n-3 fatty acid. Back transfer is set to
zero in every case. Half-lives for 18:3*, 20:5*, 22:5* and
22:6* were 1, 67, 58, and 20 h, respectively, with
coef®cients of variation averaging about 25%. More
importantly, ef®ciency of conversion of 18:3n-3* to
20:5n-3* was only about 0.2%, while 63% of 20:5n-3*
was converted to 22:5n-3*, and 37% of that was
converted to 22:6n-3*. Overall conversion ef®ciency for
18:3n-3?22:6n-3, the product of these ®gures, is
0.047%. Twenty-three percent of 20:5n-3, however,
was converted to 22:6n-3, showing that the limit in
conversion, at least as observed from plasma measure-
ments, is between 18:3n-3 and 20:5n-3. These are
probably the most reliable estimates to date on conver-
sion of 18:3n-3 to n-3 LCP in adults.
A controlled dietary study examined whether feeding of
18:3n-3 or 18:3n-6 or both to Dutch vegans for 4 weeks
altered plasma fatty acids [26 . .]. No changes in 22:6n-3
were detected, and a statistically signi®cant but meta-
bolically insigni®cant change in 20:5n-3 was observed. A
similar recent study in Australian vegetarians failed to
show any increase in serum or platelet phospholipid
22:6n-3 [27]. These studies of vegans/vegetarians extend
those previous studies of omnivores, since vegans/
vegetarians are expected to be optimal LCP synthe-
sizers. Based on geographic location, the participants in
these studies are possibly ®rst generation vegans and
thus they may not have the metabolic potential to
upregulate LCP synthesis, which may be found in
traditionally vegan cultures. This report very usefully
presents in tabular form (their Table 10) a summary of
previous 18:3n-3 supplementation trials and their ®nd-
ings. It shows that with supplementation of 7±25 g/day
lasting for 21±56 days, no studies showed an increase in
22:6n-3, though ®ve of six reporting 20:5n-3 concentra-
tions showed increases in this LCP, and three of six
showed increases in 22:5n-3. Another review also
includes a list of 10 supplementation trials (their Table
IV), only three of which overlap with the previous list. In
the seven additional studies, no signi®cant increases in
22:6n-3 were observed. A study not included in either of
these tables did ®nd serum increases in 22:6n-3 after
10 months of feeding of 18:3n-3, 3 g/day from perilla oil,
to elderly volunteers (age 67±91) in Japan [28]. This
latter study is somewhat surprising since the regular
intake of n-3 LCP from ®sh was considerable in these
volunteers. Once again, increases in 20:5n-3 in response
to 18:3n-3 supplementation were commonly observed.
Failure to elevate 22:6n-3 blood-compartment concen-
trations by 18:3n-3 supplementation does not necessarily
mean that 22:6n-3 concentrations do not increase in
tissues. Conversion and conservation of 18:3n-3 may be
ef®cient in developing neural tissue and in very active
tissues such as retina which actively recycles 22:6n-3.
Reliable measurements of these processes, however, are
not possible without access to tissue samples and
therefore are not possible for most tissues in humans.
Animal studies of conversion ef®ciency are of limited
value because of physiological differences, as cited
below.
Other metabolic fates of 18:3n-3:
18:3n-3 oxidation
Though its role as a n-3 LCP precursor is well known,
18:3n-3 is normally used for energy and as a carbon
source to a greater extent than for direct biosynthesis.
Total oxidation studies based on administration of [13C]-
18:3n-3 (18:3*) and measurement of total expired 13CO2
( .CO2) permit an accurate assessment of the quantitative
signi®cance of one fate for 18:3n-3 in the whole body.
This is the only one of the three metabolic fates for
18:3n-3 that is, in principle, accessible to accurate,
minimally invasive whole body measurements.
In adult humans, about 24% of ingested 18:3* was
oxidized completely to CO2 within the ®rst 10±24 h in
two studies [29 .,30 .]. One of these studies reported that
the diet consisted of 40% energy as fat with an 18:2n-6/
18:3n-3 ratio of 11:1 and an 18:3n-3 content of 0.7%
130 Lipid metabolism
energy, which is typical of a western diet [29 .]. In both
studies, breath CO2 returned to near baseline at the
conclusion of the collection period. A study of normal
and x-linked retinitis pigmentosa adult males reported
that cumulative .CO2 collected to a plateau at 7 days
was about 60% of the ingested dose [23 . .]. This is
consistent with recent data appearing in abstract form,
which also details collected breath for 7 days and shows
that oxidation of 18:3* totaled 69+29% [31].
A recent study of adults shows convincingly that the
absolute amount of corn oil ingested in¯uences the
proportion oxidized in the immediate post-prandial
period [32 .]. Corn oil typically consists of 18:2n-6 and
18:1n-9, and in this study labeled [1-13C]-palmitic acid
(16:0) was supplemented for technical reasons. Oxidation
decreased from 38% for a 20 g fat load to 14% for a 137 g
fat load. Interestingly, breath CO2 isotopic enrichment,
indicative of fat oxidation, plateaued at 8 h post-dose,
suggesting that the quoted percentage oxidation of these
fats may be considerably greater after the period of post-
prandial lipemia, consistent with the abstract report from
the longer-term study [31]. In most cases, oxidation of
18:3n-3 is greater than or equal to that of 18:2n-6. This
study clearly indicates that total fat load in test meals
must be considered in future investigations of fatty acid
oxidation [32 .].
Acetate resulting from partial oxidation of 18:3n-3 and
recycled as a carbon source is best known for de-novo
lipid synthesis of saturated and monounsaturated fatty
acids and cholesterol. The relative amount of recycled
18:3* appearing in saturates and monounsaturates has
been measured as high as 30-fold in the liver and brain
of neonatal rodents and three-fold in neonatal primates
[33,34] compared with the amount of 18:3n-3* appearing
in n-3 LCP.
Taken together, these data suggest that more than 75%
of ingested 18:3n-3 is shunted to b-oxidation and
relatively little is used for synthesis of n-3 LCP. The
extent to which these alternative fates for 18:3n-3 are
obligatory is unknown. It is postulated that excess
18:3n-3 is oxidized; recycling of 18:3n-3 at minimal
intake levels has not been reported. 18:2n-6 is however
oxidized and used as a carbon source even under
conditions of extreme de®ciency in rats and therefore
appears to be obligatory [35 .]. Analogous processes may
operate for 18:3n-3. Among the reasons for obligatory
recycling of 18:3 is for use as a carbon source for the
growing brain. Support for this view is the observation
that brain levels of 18:3n-3 are very low in all species
even though dietary 18:3n-3, unlike saturates and
monounsaturates, traverses the blood±brain barrier [36].
Further work pinpointing the site of 18:3n-3 recycling in
the brain is warranted.
Factors influencing conversion efficiency
As expected, metabolic regulation exerts control over
conversion ef®ciency in response to demand for LCP
and dietary fatty acid composition. Genetic factors may
also be relevant in speci®c populations.
Competition with 18:2n-6
In spite of the structural similarities, the tissue concen-
trations of n-3 and n-6 PUFA are very different and their
behavior as a result of experimental treatments is often
reciprocal. An early demonstration of their competitive
nature showed that an increase in dietary concentrations
of 18:2n-6 causes a decrease in products of n-3 LCP, and
vice versa [37]. In more recent years, data have
suggested that increases in dietary LCP decrease
conversion of C18 precursors to LCP, presumably due
to product downregulation of biosynthetic enzymes,
speci®cally desaturation and elongation systems. Thus,
discussions of conversion ef®ciency must be in the
context of a speci®c dietary fatty acid composition, fat
content and physiological state. Optimal conversion of
18:3n-3 to n-3 LCP is expected when the diet is low in
both n-6 fatty acids, particularly 18:2n-6, and in n-3 LCP.
Dietary increases in 18:3n-3 and 18:2n-6 generally
should result in decreases in 18:3n-3 conversion ef®-
ciency.
Competition with long chain polyunsaturates
The best dietary sources of n-3 LCP are marine foods,
particularly fatty ®sh such as salmon, some cuts of tuna,
mackerel and herring. Terrestrial meats (beef, pork,
chicken), dairy products, and eggs contain low but
signi®cant amounts of both n-6 and n-3 LCP, but are
highly variable in their concentrations. LCP concentra-
tions can be increased by judicious choice of production
practice, for instance feeding of linseeds to pigs, which
increases some tissue n-3 LCP [38 .], or enrichment of
n-3 fatty acids in eggs by supplementation of laying
hens' diets with cod liver, canola, or linseed oils [39].
Vegan diets do not contain signi®cant concentrations of
LCP and therefore those on vegan diets must bio-
synthesize all their LCP from C18 precursors. Overall
LCP synthesis of vegans is therefore expected to be
ef®cient. Due to the competition of n-6 and n-3 PUFA,
however, high ratios of 18:2n-6/18:3n-3 are expected to
inhibit the conversion ef®ciency of 18:3n-3. The n-3
LCP status of vegans tends to be half that of omnivores
[40].
Traditional diets
PUFA metabolism in various species suggests that
traditional diets exert evolutionary pressure on 18:3n-3
metabolism. For instance, compared with omnivores,
cats have a barely detectable capacity for LCP synthesis,
a physiological feature rationalized by their exclusive
diet of meat that makes them obligate carnivores [41]. It
 Conversion of a-linolenic acid to long chain n-3 fatty acids Brenna 131
has long been suspected that traditional human diets
may exert natural selection pressure on LCP biosyn-
thetic enzyme activity, and there is evidence for this
hypothesis in primarily carnivorous arctic North Amer-
ican native populations [2,42]. It is therefore possible
that human populations subsisting on vegan diets for
many generations for environmental, religious, or other
reasons may have a greater capacity for LCP synthesis.
Beyond pressure on gene activity, nutritional status can
affect desaturase enzyme activity [43].
Conclusions
Humans of all ages, including preterms and very likely
fetuses, convert 18:3n-3 to 22:6n-3. Available data
indicate that conversion of 18:3n-3 to 20:5n-3, 22:5n-3,
and 22:6n-3 is a minor quantitative fate of 18:3n-3. Total
oxidation and partial oxidation with carbon recycling
appear to be predominant mechanisms and may be
important processes per se. Conversion of 18:3n-3 to n-3
LCP is progressively less ef®cient in the order consistent
with the sequence of n-3 PUFA in the agreed-upon
pathway leading to 22:6n-3, so that 22:6n-3 is the least
ef®ciently formed n-3 LCP in humans. Conversion
ef®ciency also appears to decrease as infants mature,
and may be even less ef®cient in omnivorous adults
where most estimates put it at around 1% or less of
dietary consumption. A relatively high dietary n-6/n-3
ratio characteristic of modern diets is expected to reduce
ef®ciency yet further. Consumption of preformed n-3
LCP is a far more ef®cient way to improve n-3 LCP
status. These observations have direct implications for
in¯uence of low n-3 LCP levels in neural development
and progression of chronic disease.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
. of special interest
..
of outstanding interest
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132 Lipid metabolism
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26 Fokkema MR, Brouwer DA, Hasperhoven MB, et al. Short-term supplementa-
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40% fat calories, does not depend on label position, and peaks at 4±6 h. This
contrasts with 34% oxidation of 12:0 and 16% for 18:2.
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12trans-18:3 and 9cis, 12trans-18:2. When consumed with 30 g olive oil, low in
linolenic acid and linoleic acid, about 24% of linolenic acid and the trans isomers
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decreasing proportion of the ingested fat is oxidized with increasing oral load.
Although the average amount oxidized was about 25%, the proportion ranged
from 38+15 to 14+4% for ingested loads of 20 and 137 g, respectively. These
differences show that partitioning is sensitive to overall fat load.
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but not 22:6 increased in muscle with no negative effects on meat quality. This
study demonstrates dose±response changes in plasma and tissue PUFA in 18:3-
supplemented non-ruminants and is an example of manipulation of animal
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