ARTICLE
Auteur(s) : Stanley I
Rapoport, Jagadeesh S Rao, Miki Igarashi
Brain Physiology and Metabolism Section, National Institute on
Aging, National Institutes of Health, Building 9, Room 1S128, 9000
Rockville Pike, Bethesda, MD 20892 USA
Introduction
Brain structure and function depend on interactions between
arachidonic acid (AA, 20:4n-6) and docosahexaenoic acid (DHA,
22:6n-3) at multiple sites [1-3]. These long-chain polyunsaturated
fatty acids (PUFAs) and their respective shorter-chain PUFA
precursors, linoleic acid (LA, 18:2n-6) and α-linolenic acid
(α-LNA, 18:3n-3), are nutritionally essential and cannot be
synthesized de novo in vertebrate tissue.
Animal studies with different proportions of PUFAs in the diet
have identified broad dietary requirements for maintaining optimal
brain function [4], and have demonstrated that metabolic and
behavioral defects arise from severe n-3 PUFA dietary deprivation.
Additionally, clinical studies indicate that low dietary
consumption of n-3 PUFAs or low plasma DHA concentrations are
correlated with a number of brain diseases and with cognitive and
behavioral defects in development and aging [5-7], and that dietary
n-3 PUFA supplementation may be beneficial in some of these
conditions [3, 8].
Effects on the brain of minor n-3 PUFA dietary deprivation
associated with small declines in plasma DHA concentrations of the
order found in the clinic have rarely been studied in animal
models. Additionally, controversy exists about which dietary PUFA
compositions are optimal for human brain function [3, 8-12]. The
liver’s in vivo capacity to convert α-LNA to DHA, or LA to AA, has
not be quantified in animals or in humans, although changes in this
capacity with development, aging or disease likely impact brain
PUFA metabolism [13-17].
To address these and related issues, we have developed methods
and models to examine PUFA metabolism in the intact organism. The
methods include brain imaging with quantitative autoradiography or
positron emission tomography (PET), intravenous injection of
radiolabeled PUFAs to examine incorporation, turnover and synthesis
rates of PUFAs in brain or liver, enzyme assays to evaluate
activities of lipid metabolizing enzymes, and molecular techniques
to examine transcriptional regulation and protein levels of these
enzymes. We have used these approaches to measure AA and DHA brain
consumption rates in unanesthetized rats and in human subjects, and
to quantify dietary effects in rats on brain and liver PUFA
metabolism. We shall discuss the results of these experiments in
this paper, when considering three general questions: (1) What are
the rates of brain consumption of AA and DHA in rats and humans in
relation to diet? (2) How does brain DHA depend on dietary n-3 PUFA
composition and the liver’s ability to convert α-LNA to DHA? (3)
How do brain lipid enzymes and trophic factors respond to dietary
n-3 PUFA deprivation?
Methods and models
AA and DHA are found in high concentrations in the
stereospecifically numbered (sn)-2 position of brain membrane
phospholipids, from where they can be released by selective
phospholipase A2 (PLA2) enzymes [18-23].
After release, most of the unesterified AA or DHA will be rapidly
reincorporated into an available lysophospholipid via the acyl-CoA
pool, through serial actions of an acyl-CoA synthetase and
acyltransferase with the consumption of two molecules of ATP (figure 1) [24]. A
small fraction, however, will be lost through any of a number of
catabolic pathways, including β-oxidation and conversion to
eicosanoids or docosanoids by cyclooxygenases (COXs),
lipoxygenases, or cytochrome P450 [25-29].
Neither AA nor DHA is converted significantly (< 1%) in brain
from its respective precursor, LA or α-LNA (figure 2) [30, 31], and
neither can be synthesized de novo in vertebrate tissue [32].
However, the quantity of AA or DHA that is lost from brain by
metabolism will be rapidly and stoichiometrically replaced by the
unesterified PUFA in plasma [33]. Replacement occurs independently
of changes in cerebral blood flow at a rate Jin (Eq. 2
below) [27, 30, 31, 34-39].
In unanesthetized rodents and in human subjects, we have
quantified Jin by infusing intravenously injected
albumin-bound radiolabeled AA or DHA, then imaging regional brain
radioactivity. We also have quantified Jin into
individual phospholipids, triacylglycerols and cholesteryl esters
of rodent liver and brain, after subjecting the organ to high
energy microwaving to stop its metabolism, then measuring PUFA
specific activities in organ lipid compartments.
For neuroimaging, an incorporation coefficient k* (ml/sec/g
brain) is calculated as regional brain radioactivity divided by the
integrated plasma radioactivity of the unesterified AA or DHA
(input function),
where t is time after beginning tracer infusion, nCi/g is brain
radioactivity at time T of sampling (often 5 min), and nCi/ml
is plasma radioactivity. Jin nmol/sec/g brain equals k*
multiplied by the unlabeled unesterified plasma AA or DHA
concentration, cplasma nmol/ml,
The half-life t1/2 is calculated from the esterified
brain concentration cbrain and the incorporation
rate,
The incorporation rate Jin, determined following the
intravenous infusion of a radiolabeled PUFA using Eq. 3, equals the
rate of PUFA loss from brain, Jloss (see above),
This is illustrated, for example, in figure 3 (left) for DHA,
where the half-life of DHA loss from rat brain was calculated from
the rate of decline of brain [4,5-3H]DHA following its
intracerebral injection [36].
Half-lives for net DHA or AA loss from brain (Eqs. 3 or 4),
which are of the order of weeks to months in rats [36, 37], are
much longer than their respective half-lives due to recycling
(deacylation-reacylation) (figure 1) [26, 40]. These
can be minutes to hours [37, 41]. Recycling is associated with
neurotransmission and rapid, neuroreceptor-initiated
PLA2-mediated release of AA or DHA from membrane
phospholipid [18, 42], and it is accompanied by high rates of ATP
consumption [43].
We have extended our in vivo fatty acid model to quantify
coefficients and rates of conversion and esterification of
circulating α-LNA to DHA into “stable” brain and liver lipids i
[16, 17, 30, 31, 44]. The appropriate equations relate
[1-14C]DHA radioactivity within “stable” lipids i
following intravenous [1-14C]α-LNA infusion, to the
organ’s integrated exposure to the tracer in plasma. For the liver,
the conversion coefficient is given in units of mL/sec/g
liver,whereas the conversion rate in units of nmol/sec/g liver
equals,where nCi/g is DHA radioactivity in “stable” lipid i, nCi/mL
is plasma radioactivity due to unesterified
[1-14C]α-LNA, and nmol/mL is the plasma concentration of
unesterified unlabeled α-LNA.
The rate of secretion by liver of the DHA that it has
synthesized from total plasma α-LNA can be estimated by summing
equations 6 for i = phospholipid, triacylglycerol and cholesteryl
ester, then dividing by a “dilution” factor [17, 27, 44]. This
factor equals the steady-state ratio of specific activity of liver
α-LNA-CoA to specific activity of plasma unesterified α-LNA, during
infusion of [1-14C]α-LNA,
Results and questions
Question 1: What are the rates of brain consumption of AA and
DHA in rats and humans in relation to diet?
Studies in unanesthetized rats
To examine how brain PUFA metabolism is related to dietary PUFA
composition, we quantified brain consumption rates of DHA in
relation to the liver’s ability to convert circulating α-LNA to DHA
in rats that had been fed, for 15 weeks post-weaning (starting at
21 days of age), one of three diets (table
1, row 1): (1) a high DHA-containing diet (DHA 2.3% of
total fatty acids, 5.1% α-LNA, 4% fat); (2) a DHA-free diet
containing 4.6% α-LNA (of total fatty acids), 10% fat; or (3) a
DHA-free diet containing 0.2% α-LNA, 10% fat. We term the latter
two diets n-3 PUFA “adequate” and “deficient”, respectively,
following the convention of Bourre [4]. The rats fed the
“deficient” compared with “adequate” diet had increased scores on
behavioral measures of depression and aggression [45].
The unesterified plasma α-LNA concentration in rats fed the n-3
PUFA “adequate” diet was 36% less than in rats fed the
DHA-containing diet, but 27 times higher than in rats fed the
“deficient” diet (table 1, row 2).
Unesterified plasma AA did not differ markedly among rats on the
three diets, whereas the plasma concentration of the AA elongation
product, docosapentaenoic acid (DPAn-6, 22:5n-6), while low in rats
fed the high DHA or n-3 PUFA “adequate” diet, equaled 8.7 nmol/mL
in rats fed the “deficient” diet (row 3, table
1).
The DHA concentration in brain phospholipid (table 1, row 4) was lower in rats fed the
“adequate” than high DHA diet, but was reduced by an additional 4.4
μmol/g in rats fed the “deficient” diet. While AA concentrations in
brain phospholipid were about the same in rats on each of the three
diets (table 1, row 5), brain DPAn-6 was
elevated by 4.2 μmol/g in rats fed the “deficient” diet,
compensating for the reduced DHA concentration.
DHA incorporation coefficients k* (Eq. 1) did not vary markedly
among the three dietary groups (table 1,
row 6), whereas the net rate of DHA incorporation into brain,
Jin, thus its rate of loss from brain, was reduced in
rats fed the deficient diet (table 1,
rows 7 and 8), due to the low plasma DHA concentration with this
diet (Eq. 2). Reduced values of Jin for DHA in rats fed
the “deficient” diet corresponded to a 3-fold prolongation of the
DHA half-life in brain phospholipid (figure 3, right) [36].
Values of Jin for AA can be found elsewhere in
unanesthetized mice and rats [34, 35, 46, 47].
Table 1 Plasma and brain parameters in unanesthetized
rats fed different diets for 15 weeks. Row 1: dietary composition;
row 2: unesterified plasma concentrations of α-LNA and DHA (in
brackets); row 3: unesterified plasma concentrations of AA and
DPAn-6 (in brackets); row 5: AA and DPAn-6 (in brackets)
concentrations in brain phospholipids; row 6: incorporation
coefficient calculated by Eq. 1; row 7, incorporation rate
calculated by Eq. 2; row 8: whole brain DHA incorporation
(consumption) rate for 1.5 g rat brain.
|
|
|
Diet during 15 weeks post-weaning
|
|
1
|
Parameter
|
Units
|
High DHA diet (5.1% α-LNA, 2.3% DHA, 4% fat)
|
High α-LNA diet (4.6% α-LNA, no DHA, 10% fat)
|
n-3 PUFA inadequate diet (0.2% α-LNA, no DHA, 10% fat)
|
|
2
|
- cplasma(α-LNA)
- [cplasma(DHA)]
|
nmol/ml
|
|
|
- 1.0 ± 0.45*
- [0.23 ± 0.10]*b
|
|
3
|
- cplasma(AA)
- [cplasma(DPAn-6]
|
nmol/ml
|
|
|
|
|
4
|
DHA concentration in brain phospholipid,
cbrain
|
μmol/g
|
|
12.0 ± 2.4d
|
7.6 ± 1.5*d
|
|
5
|
Concentrations of AA and [DPAn-6] in brain phospholipid
|
μmol/g
|
- 11.1 ± 2.9c
- [0.1 ± 0.04]c
|
- 9.4 ± 1.1d
- [0.25 ± 0.06]d
|
|
|
6
|
DHA incorporation coefficients, k*
|
ml/s/g x 10-4
|
2.2 ± 0.2f
|
1.99 ± 0.3e
|
2.83 ± 0.6*e
|
|
7
|
Rate DHA incorporation, Jin#
|
nmol/s/g x 10-4
|
17.4 ± 2.0f
|
22.0 ± 5.0e
|
0.23 ± 0.05*e
|
|
8
|
Daily rate DHA consumption by whole (1.5 g) brain
|
μmol/day
|
0.23f
|
0.29e
|
0.003e
|
PUFA consumption by the human brain
We also have determined Jin for AA and DHA in the human
brain using PET and the positron emitting tracers,
[1-11C]AA and [1-11C]DHA, respectively
[48-51] (Umhau et al., unpublished results). Whole-brain
Jin in healthy adults equaled 17.8 mg/day per 1500 g
brain for AA (figure
4) [49] and 4.6 mg/day per 1500 g brain for DHA (Umhau
et al., unpublished results). Furthermore, Jin for AA
did not decline with healthy aging [49].
Dietary intakes of n-3 PUFAs for maintaining optimal human brain
PUFA metabolism are not agreed on, but they now might be estimated
by relating dietary PUFA composition to PET-determined brain DHA
incorporation (consumption) rates. Different committees have
recommended eicosapentaenoic acid (EPA, 20:5n-3) + DHA intakes of
0.11-0.16 g/day [52], 0.2 g/day [10], 0.65 g/day [11], and
1.6 g/day [12]. Another committee recommended that adult men
and women should consume 1.6 g/day and 1.1 g/day, respectively, of
α-LNA, plus an additional 10% (0.16-0.11 g) representing EPA + DHA
[52]. Our PET-determined Jin for DHA, 4.6 mg/day
(see above), equals 2.5-5% of the estimated average daily dietary
intake of EPA + DHA in the United States, 100-200 mg/day [9].
Question 2: How does brain DHA depend on dietary n-3 PUFA
composition and the liver’s ability to convert α-LNA to DHA?
A large fraction of the world’s population does not eat meat or
fish for various reasons, but the effects, if any, of low dietary
levels of DHA and EPA on their brain function have not been
identified [53]. In such subjects, the brain’s DHA content must
depend on the liver’s ability to synthesize and secrete DHA from
circulating α-LNA.
To address the issue of liver synthesis, we estimated the
liver’s ability to synthesize DHA from α-LNA in unanesthetized rats
fed each of the three diets discussed above. Row 2 of table 2 gives the calculated conversion
coefficients (Eq. 5) of unesterified α-LNA to DHA into “stable”
liver lipids i = phospholipid (PL) and triacylglycerol (TG),
whereas row 3 gives the sum of rates of DHA synthesis followed by
incorporation (Eq. 6) into these lipids. Assuming that the liver
secretes its newly formed esterified DHA within circulating
lipoproteins [54], row 4 presents liver DHA secretion rates,
calculated by Eq. 7, in units of μmol/day per 11.5 g rat liver.
Conversion coefficients of unesterified plasma α-LNA into liver
phospholipid and triacylglycerol DHA were 2-fold greater in rats
fed the n-3 PUFA “adequate” than high DHA diet, and were further
increased 7-fold in rats fed the “deficient” diet. The increases
corresponded to increased liver activities of the Δ5 and Δ6
desaturases and elongases 2 and 5 that mediate conversion of α-LNA
to DHA and of LA to AA [55] (Igarashi et al., unpublished results).
Net liver DHA synthesis and secretion rates were much less in rats
on the n-3 PUFA “deficient” than “adequate” diet (table 2, rows 3 and 4), reflecting the low plasma
α-LNA concentration with the “deficient” diet (Eq. 6). The liver’s
net DHA synthesis rate in rats fed the DHA-free n-3 PUFA “adequate”
diet was about 10-fold the brain’s DHA consumption rate (table 1, row 8). Thus, liver secretion was
sufficient to supply the brain’s DHA.
In summary, in rats fed an n-3 PUFA “adequate” diet containing
4.6% α-LNA, brain DHA is maintained entirely by the DHA formed and
secreted from circulating α-LNA by the liver. When dietary α-LNA is
reduced, the liver increases its coefficients for DHA synthesis by
upregulating activities of relevant desaturases and elongases.
Table 2 Calculated liver parameters in unanesthetized
rats fed each of three diets, correspond to plasma and brain data
of table 1a. Row 2: conversion
coefficients calculated by Eq. 5; rows 3 and 4: secretion rates per
g and per total liver, calculated by Eq. 6.
|
|
|
Diet During 15 Weeks Post-weaning
|
|
1
|
Parameter
|
Units
|
High DHA diet (5.1% α-LNA, 2.3% DHA, 4% fat)a
|
High α-LNA diet (4.6% α-LNA, no DHA, 10%
fat)b
|
n-3 PUFA inadequate diet (0.2% α-LNA, no DHA, 10%
fat)b
|
|
2
|
Conversion coefficients liver, (i = PL, TG)
|
ml/s/g × 10-4
|
0.03, 0.1
|
0.053, 0.219
|
0.44, 1.45
|
|
3
|
Net DHA conversion rate per g liver
|
nmol/s/g × 10-4
|
6.6
|
7.45
|
1.99
|
|
4
|
Net daily DHA secretion rate, per 11.5 g rat
liver#
|
μmol/day
|
1.57
|
2.19
|
0.82
|
Question 3: How do brain lipid enzymes and trophic factors
respond to dietary n-3 PUFA deprivation?
Enzymes of the brain AA and DHA cascades
DHA-loss half life in rat brain (Eq. 4) was prolonged 3-fold in
rats fed the n-3 PUFA “deficient” compared with the “adequate” diet
(figure 3,
right) [36]. This prolongation resulted from the brain’s ability to
downregulate expression of some of its DHA-metabolizing enzymes.
Thus, in rats fed the “deficient” compared with “adequate” diet,
brain mRNA, protein and activity levels of DHA-selective
Ca2+-independent phospholipase A2
(iPLA2) [22] and of COX-1 were downregulated [56], as
illustrated in figure
5. The two affected enzymes are known to be functionally
coupled in different tissues [57].
Also illustrated in figure 5, the 15-week n-3
PUFA deficiency upregulated brain mRNA, protein and activity levels
of AA-selective cPLA2, secretory sPLA2 and
COX-2 [56], enzymes that often are functionally coupled [23, 57,
58]. These changes, in the context of an increased brain DPAn-6
concentration (table 1, row 3), imply
that the “deficient” diet upregulated brain n-6 PUFA
metabolism.
Excess AA metabolism can contribute to neuronal damage in
experimental ischemia, glutamate excitotoxicity, neuroinflammation,
and cerebral trauma [42, 59-63]. This implies that n-3 PUFA dietary
deficiency would increase brain vulnerability to these insults by
increasing brain n-6 PUFA metabolism, whereas dietary n-3 PUFA
supplementation would be neuroprotective. In this regard, a low
dietary n-3 PUFA content has been suggested to increase brain
vulnerability in a number of human diseases, including Alzheimer
disease and bipolar disorder, in which neuroinflammation and
excitotoxicity play a role, and n-3 PUFA supplementation may be
helpful in some of these diseases [5, 6, 64, 65].
BDNF and CREB
Another way in which dietary n-3 PUFAs may be neuroprotective is by
upregulating brain trophic factors. For example, brain derived
neurotrophic factor (BDNF) promotes neuronal survival, plasticity,
differentiation and growth [66]. Transcription of the BDNF gene is
regulated by the cAMP response element-binding protein (CREB),
following CREB’s phosphorylation by protein kinases including p38
mitogen activated protein (MAP) kinase [67]. In rats fed the n-3
PUFA “deficient” compared with “adequate” diet, figure 6 shows that brain
mRNA and protein levels of BDNF, CREB DNA binding activity, the
phosphorylated CREB protein level and p38 MAP kinase activity were
reduced significantly [67].
In summary, rats subjected to our 15-week dietary n-3 PUFA
deprivation have a reduced brain DHA concentration and a prolonged
DHA half-life, accompanied by reduced activities of presumably
DHA-selective iPLA2 and COX-1; an increased brain DPAn-6
concentration accompanied by increased activities of AA-selective
cPLA2, sPLA2 and COX-2; and reduced
expression of BDNF that corresponds to reduced CREB DNA binding
activity and p38 MAP-kinase activity.
Conclusions
In response to each of the three questions presented in the
Introduction, we have shown that: (1) Regional and global brain AA
and DHA consumption rates can be and have been quantified in
unanesthetized rats, and in humans using PET. (2) In the absence of
dietary DHA, a normal brain DHA content can be maintained by liver
conversion of α-LNA to circulating DHA, provided sufficient α-LNA
is in the diet. Liver but not brain conversion coefficients are
increased by further α-LNA deprivation, in relation to increased
expression of liver elongases and desaturases. (3) Brain DHA
reduction caused by 15 weeks of dietary n-3 PUFA deprivation in
rats is associated with slowed DHA loss from brain and reduced
expression of presumably DHA-metabolizing enzymes, tending to
conserve brain DHA, by increased expression of AA-metabolizing
enzymes and a high DPAn-6 concentration, and by reduced BDNF,
phospho-CREB and p38 MAP kinase activity levels. Some of these
changes are consistent with neuroprotective effects of n-3 PUFAs.
Now that appropriate quantitative techniques are available for
studying the relations among brain and liver PUFA metabolism and
diet in animals and humans, future studies using these techniques
might address a number of additional relevant questions: (1) To
what extent does the liver convert EPA to DHA under different
dietary conditions? (2) What are the effects of graded n-3 PUFA
dietary deprivation on the markers and kinetics of brain metabolism
and function that we have presented in this paper? (3) What are the
effects on these markers of dietary n-6 PUFA deprivation? (4) How
do liver conversion rates of α-LNA and EPA to secreted DHA vary
with age and liver disease? (5) In humans, how do brain AA and DHA
consumption rates change with aging or disease, and how might human
diets be tailored to maintain normal consumption rates with these
variable conditions?
Acknowledgements
This work was supported by the Intramural Program of the National
Institute on Aging, National Institutes of Health, Bethesda,
Maryland, USA. We thank Dr. Richard Bazinet, Dr. David Purdon and
Dr. Malden Nesheim for their helpful comments.
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Abbreviations: AA,
arachidonic acid; DHA, docosahexaenoic acid; LA, linoleic acid;
PET, positron emission tomography; PUFA, polyunsaturated fatty
acid; PLA2, phospholipase A2; α-LNA,
α-linolenic acid; BDNF, brain derived nerve growth factor; CREB,
cAMP response element-binding protein; EPA, eicosapentaenoic acid;
DPA, docosapentaenoic acid; MAP, mitogen activated protein; sn,
stereospecifically numbered; COX, cyclooxygenase
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