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Am J Physiol Heart Circ Physiol 309: H1112–H1114, 2015;
doi:10.1152/ajpheart.00620.2015.
Editorial Focus
Even is better than odd: one fat may conceal another
Christophe Beauloye,1,2 Sandrine Horman,1 and Luc Bertrand1
1
Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain,
Brussels, Belgium; and 2Division of Cardiology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
Address for reprint requests and other correspondence: L. Bertrand, Pole of
Cardiovascular Research, Inst. de Recherche Expérimentale et Clinique, Univ.
catholique de Louvain, Ave. Hippocrate, 55, B1.55.05, B-1200, Brussels,
Belgium (e-mail: [email protected]).
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their uptake through sarcolemmal and mitochondrial membranes, bypassing the rate-limiting membrane transporting system CPT1 (Fig. 1). Consequently, MCFAs are promptly taken
up by mitochondria, where they are easily and preferentially
oxidized, the rate of their oxidation being exclusively determined by their blood concentrations.
In the current issue of the American Journal of PhysiologyHeart and Circulatory Physiology, Kajimoto et al. (12) nicely
evaluated the impact of MCFA infusion on myocardial metabolism and energy state during extracorporeal membrane oxygenation (ECMO), a common mechanical circulatory support
system of the failing heart in neonatal and pediatric population.
ECMO, when prolonged, is characterized by a high level of
mortality and morbidity (7, 20). The emergence of an imbalance between energy production and consumption under these
conditions is assumed to delay left ventricular recovery and is
responsible for ECMO circuit-weaning failure. This is the
reason why it is worthwhile to identify metabolic therapies able
to increase CAC intermediate concentration and to intensify
substrate oxidation in the goal to enhance ATP production and
to improve function recovery after ECMO. Kajimoto and
collaborators (13, 14) already previously showed that ECMO is
characterized by a metabolic adaptation that promotes fatty
acid oxidation. Using an infant swine ECMO model, they also
showed that when supplied at physiological concentrations (0.4
mM), octanoate, a typical dietary even-numbered MCFA, provides 60% of the acetyl-CoA molecules entering to the CAC,
whereas long-chain fatty acids only contribute for 12% (14). In
their article, Kajimoto and colleagues (212) went further and
nicely compared the action of the even-numbered octanoate
with that of heptanoate, an odd-numbered MCFA (12). The
rationale of this study resides in the theoretical different fate of
odd- and even-numbered MCFAs (Fig. 1). Even-numbered
MCFAs are fully oxidized into acetyl-CoA (octanoate, containing 8 carbons gives 4 acetyl-CoAs) that can enter into the
CAC. On the other hand, odd-numbered MCFAs are oxidized
into both acetyl-CoA and propionyl-CoA (heptanoate, containing 7 carbons, provides 2 acetyl-CoAs and 1 propionyl-CoA).
Subsequently, propionyl-CoA can be metabolized into succinyl-CoA, via an anaplerotic reaction that contributes to the
formation of CAC intermediates (2, 5). Already suggested in
the past (3, 17), the authors of the present study hypothesized
that producing CAC intermediates in addition to feed CAC
with acetyl-CoA would give a evident energetic advantage to
the heart. Elegantly combining different 13C-labeled substrates,
13
C-nuclear magnetic resonance and gas chromatography-mass
spectrometry approaches, Kajimoto et al. (12) demonstrated
that octanoate significantly increases cardiac energy state under
ECMO, whereas heptanoate fails to do so. This specific octanoate-mediated elevation in ATP-to-ADP ratio is accompanied by an increase in citrate concentration. The authors
postulated that this might result from the increase in leucine
oxidation eventually observed (Fig. 1). By contrast, anaplerosis
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is tightly interconnected to substrate
metabolism. Indeed, the heart is the highest energy-consuming
organ, producing and instantaneously consuming between 3.5
to 5 kg of ATP per day (in human) to sustain its contractile
function (21). In other words, the daily amount of ATP turned
over in the heart is equivalent to 15-20 times its own weight
(15). Actually, the heart uses its entire ATP pool in only 10 s
(19). Continuous and substantial ATP production is then an
absolute requirement for efficient heart contraction. Almost all
(⬎95%) ATP production is provided from the oxidation of
carbon substrates into the mitochondria via the citric acid cycle
(CAC). Inasmuch as the intracellular bioenergetic reserve capacity (mainly constituted by glycogen and intracellular lipid
pools) of the cardiomyocytes is relatively limited, the heart
needs to purchase available substrates from the circulation.
The heart can use a variety of different types of energyproducing substrates depending on their availability and hormonal status. These include carbohydrates (glucose, pyruvate,
and lactate), lipids, ketone bodies, and even certain amino
acids like leucine, all providing acetyl-coenzyme A (CoA) to
feed the CAC. Under resting condition, 60 –70% of ATP
generation in mitochondrion comes from ␤-oxidation of fatty
acids and 30 – 40% from carbohydrates. This preference for
fatty acids as energetic substrate is due to the fact that fatty acid
oxidation inhibits glucose use by a mechanism named Randle
cycle (10). The most abundant fatty acid that can be found in
the circulation is the long-chain monounsaturated oleate (19).
Even if requiring more oxygen than carbohydrates, such longchain fatty acid is efficiently oxidized by the heart, giving
around 6.6 molecules of ATP per fatty acid carbon (in comparison to 5.2 ATP/carbon for glucose) (6). One of the main
rate-limiting steps of the oxidation of long-chain fatty acids is
their import into the mitochondria, which is mediated by the
carnitoyl palmitoyltransferase 1 (CPT1). Long-chain fatty acids, which are initially esterified to CoA, are used by CPT1 to
produce long-chain acylcarnitines that are able to shuttle into
the mitochondria (Fig. 1). CPT1 is allosterically, negatively
regulated by malonyl-CoA, reducing long-chain fatty acid
oxidation when the concentration of this molecule rises in the
cell.
Besides long-chain fatty acids, we can also find mediumchain fatty acids (MCFAs), which appear to be a promising
metabolic therapy in cardiac diseases (11, 16). In contrast to
long-chain fatty acids, MCFAs are minor components of usual
human diet but can be found in large amount in coconut oil,
which contains over 50% MCFAs. MCFAs also possess particular metabolic properties, distinct from those of long-chain
fatty acids. Indeed, MCFAs do not depend on transporters for
CARDIAC WORK EFFICIENCY
Editorial Focus
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Propionyl-CoA
βOx
Odd-numbered MCFAs
(Heptanoate)
Anaplerosis
Succinyl-CoA
Cytosol
Succinate
α-KG
Fumarate
Citrate
Even-numbered MCFAs
(Octanoate)
Malate
OAA
Leucine
CPT2
CPT1
LCFAs
βOx
βOx
ATP
Acetyl-CoA
GOx
Mitochondrial matrix
Glucose
does not seem to play an important role because both MCFAs
equally promote this metabolic pathway.
These results are puzzling because they contradict the usually accepted notions related to MCFA metabolism. First,
odd-numbered but not even-numbered MCFAs are supposed to
promote anaplerosis and succinyl-CoA production. This seems
clearly not so simple with an efficient anaplerosis induced by
even-numbered MCFAs via a mechanism that still needs to be
determined (Fig. 1). Second, the role of anaplerosis is to
replenish CAC intermediates that are regularly extracted for
other biosynthesis. Increasing anaplerosis is then supposed to
maintain CAC intermediate pool promoting efficient ATP
production. However, the present study reveals that anaplerotic
rate is similar for heptanoate and octanoate, whereas only the
latter increases energy state of the ECMO heart. Kajimoto and
collaborators (12) proposed that the increase in anaplerosis
could be linked to the increase in expression of propionyl-CoA
carboxylase-␣, which converts propionyl-CoA to succinylCoA through methylmalonyl-CoA, but this connection remains
to be established. Similar surprising data have been obtained
by Okere and colleagues (22) who compared the impact of
even- (hexanoate) and odd-numbered (heptanoate) MCFAs in
an in vivo myocardial ischemia-reperfusion model in swine.
Both MCFAs were able to increase CAC intermediate concentrations, but only even-numbered MCFA was able to increase
succinyl-CoA concentration.
It has to be noted that none of the MCFAs tested in the study
of Okere et al. (22) conferred a significant improvement in
cardiac function after reperfusion. By contrast, another study
performed in an ex vivo-perfused ischemia-reperfusion model
of diabetic rat heart (8) showed that octanoate increases longchain fatty-acid oxidation, reduces glucose oxidation, and improves postischemic cardiac function recovery. Similarly, Labarthe et al. (17) showed in a model of ex vivo-working
hypertensive hearts subjected to acute adrenergic stimulation
that octanoate improves cardiac function. Kajimoto and colleagues (12) did not see any beneficial action of even- and
odd-numbered MCFAs on cardiac function parameters of unloaded ECMO hearts, but they did not evaluate them after
pressure and volume reloading. When we take into account all
these apparent conflicting results, which have been obtained in
different pathological models and/or following distinct experimental procedures, it is difficult to definitively conclude on the
putative cardioprotective action of even- and odd-numbered
MCFAs.
Another intriguing result obtained by Kajimoto and collaborators (12) is the fact that the sole CAC intermediate really
increased by MCFA treatment is citrate, which is elevated by
octanoate but not by heptanoate. The increase in leucine
oxidation found in octanoate treatment is the element proposed
by the authors to explain such rise in citrate concentration via
a modification in acetyl-CoA production.
AJP-Heart Circ Physiol • doi:10.1152/ajpheart.00620.2015 • www.ajpheart.org
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CAC
Fig. 1. Mitochondrial metabolism of energyproviding substrates in cardiomyocyte and
particular action of even- and odd-numbered
medium-chain fatty acids (MCFAs) under extracorporeal membrane oxygenation. Black,
white, and gray circles represent substrate
carbons generating acetyl-CoA (black and
white) or propionyl-CoA (gray). Dashed blue
lines represent the stimulatory action of evennumbered MCFAs on leucine oxidation and
anaplerosis. The exact molecular mechanisms
involved in these effects are not yet fully
identified. ␣KG, ␣-ketoglutarate; ␤Ox, fattyacid ␤-oxidation; CAC, citric acid cycle;
CPT, carnitine palmitoyltransferase; GOx,
glucose oxidation; LCFAs, long-chain fatty
acids; OAA, oxaloacetate. Figure image is
largely inspired from Kajimoto et al. (12).
Editorial Focus
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ACKNOWLEDGMENTS
C. Beauloye is a postdoctoral fellow, S. Horman is a research associate, and
L. Bertrand is senior research associate from Fonds National de la Recherche
Scientifique (Belgium).
GRANTS
This work was supported by grants from Fonds National de la Recherche
Scientifique et Médicale (Belgium), Action de Recherche Concertée (Belgium), and an unrestricted grant from Astra-Zeneca (Belgium).
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
S.H., C.B. and L.B. drafted, edited, revised, and approved final version of
manuscript.
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The same research team (18) recently published another
interesting study in the American Journal of Physiology-Heart
and Circulatory Physiology. Using the same ECMO swine
model, they showed that pyruvate supplementation promotes
anaplerosis and increased CAC intermediates without any
significant increase in pyruvate oxidation. This is accompanied
by the increase of the AMP-activated protein kinase and
O-GlcNAcylation pathways, two mechanisms playing an important role in the regulation of metabolism and cardiac function (1, 4, 9).
To conclude, numerous questions remain. How do evennumbered MCFAs promote anaplerosis? Does the increase in
leucine oxidation really explain the increase in citrate concentration found with octanoate treatment? Is there any gain of
increasing energetic state using even-numbered MCFA treatment during ECMO weaning? Does pyruvate act similarly to
octanoate? Do AMP-activated protein kinase and O-GlcNAcylation play a role in the action of MCFAs on metabolic
parameters? Are these metabolic alterations induced by MCFAs also present in other pathological situations? Do they
differentially give any real benefits in term of cardiac function
maintenance or recovery? This article by Kajimoto et al. (12)
represents a good start, but long is the road for the full
comprehension of myocardial metabolism of MCFAs and their
impact on cardiac function under both physiological and pathological conditions.