Even is better than odd: one fat may conceal another.

Abstract

Editorial FocusEven is better than odd: one fat may conceal anotherChristophe Beauloye, Sandrine Horman, and Luc BertrandChristophe BeauloyePole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium; and Division of Cardiology, Cliniques Universitaires Saint-Luc, Brussels, Belgium, Sandrine HormanPole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium; and , and Luc BertrandPole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium; and Published Online:01 Oct 2015https://doi.org/10.1152/ajpheart.00620.2015This is the final version - click for previous versionMoreSectionsPDF (81 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat cardiac work efficiency 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 energy-producing 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 β-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 long-chain 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.Fig. 1.Mitochondrial metabolism of energy-providing 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 even-numbered MCFAs on leucine oxidation and anaplerosis. The exact molecular mechanisms involved in these effects are not yet fully identified. αKG, α-ketoglutarate; βOx, fatty-acid β-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).Download figureDownload PowerPointBesides long-chain fatty acids, we can also find medium-chain 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 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 Physiology-Heart 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, 13C-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 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-α, which converts propionyl-CoA to succinyl-CoA 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 long-chain 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.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 even-numbered 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.GRANTSThis 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).DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the author(s).AUTHOR CONTRIBUTIONSS.H., C.B. and L.B. drafted, edited, revised, and approved final version of manuscript.ACKNOWLEDGMENTSC. 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).REFERENCES1. Beauloye C, Bertrand L, Horman S, Hue L. 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Differential effects of heptanoate and hexanoate on myocardial citric acid cycle intermediates following ischemia-reperfusion. J Appl Physiol 100: 76–82, 2006.Link | ISI | Google ScholarAUTHOR NOTESAddress 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: luc.[email protected]be). Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationCited ByMicrobiota and Neurological Disorders: A Gut FeelingBioResearch Open Access, Vol. 5, No. 1 More from this issue > Volume 309Issue 7October 2015Pages H1112-H1114 Copyright & PermissionsCopyright © 2015 the American Physiological Societyhttps://doi.org/10.1152/ajpheart.00620.2015PubMed26297227History Published online 1 October 2015 Published in print 1 October 2015 Metrics