Carnitine Acetyltransferase is not a Cytosolic Enzyme in Rat Heart and Therefore Cannot Function in the Energy-linked Regulation of Cardiac Fatty Acid Oxidation

Abbas, Azfar S; Wu, Guoxin; Schulz, Horst

doi:10.1006/jmcc.1998.0693

Cited by 26 publications

(28 citation statements)

References 4 publications

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“…We showed that it is possible to estimate myocardial V TCA in vivo through the time-resolved 13 C MRS measurement of [5][6][7][8][9][10][11][12][13] C]citrate following the injection of hyperpolarized [1-13 C]acetate. V TCA and the dynamics of 13 C citrate labeling were independent on the amount of injected substrate and did not correlate with the dynamics of 13 C acetylcarnitine labeling.…”

Section: Resultsmentioning

confidence: 99%

“…The signal decay of precursor and metabolites results from a combination of the effects of longitudinal relaxation (characterized by the time constant T 1 ), RF excitation, and biochemical conversion and all time courses were corrected for the effect of repeated RF excitations. The T 1 of [1-13 C]acetylcarnitine was set to 14.9 s, as previously determined in vivo [35], and that of [5][6][7][8][9][10][11][12][13] C]citrate to 20 s [46]. The acetate signal decay was treated as free parameter.…”

Section: Discussionmentioning

confidence: 99%

“…Since the inner mitochondrial membrane is impermeable to acetylCoA, an excess in acetylCoA can be transferred to the cytosol via a carnitine mediated acetyltransferase system [8]. The conversion of acetylCoA to acetylcarnitine is catalyzed by carnitine acetyl transferase (CAT), an enzyme largely found in heart mitochondria, peroxisomes, the endoplasmic reticular lumen but not in the cytosol [9,10]. The shuttling of acetylcarnitine across mitochondrial membranes is an exchange process mediated by acetylcarnitine translocase (ATL).…”

Section: Introductionmentioning

confidence: 99%

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Direct noninvasive estimation of myocardial tricarboxylic acid cycle flux in vivo using hyperpolarized 13C magnetic resonance

Bastiaansen

Tian

Lei

et al. 2015

Journal of Molecular and Cellular Cardiology

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Background: The heart relies on continuous energy production and imbalances herein impair cardiac function directly. The tricarboxylic acid (TCA) cycle is the primary means of energy generation in the healthy myocardium, but direct noninvasive quantification of metabolic fluxes is challenging due to the low concentration of most metabolites. Hyperpolarized 13 C magnetic resonance spectroscopy (MRS) provides the opportunity to measure cellular metabolism in real time in vivo. The aim of this work was to noninvasively measure myocardial TCA cycle flux (V TCA ) in vivo within a single minute. Methods and results: Hyperpolarized [1-13 C]acetate was administered at different concentrations in healthy rats. 13C incorporation into [1-13 C]acetylcarnitine and the TCA cycle intermediate [5-13 C]citrate was dynamically detected in vivo with a time resolution of 3 s. Different kinetic models were established and evaluated to determine the metabolic fluxes by simultaneously fitting the evolution of the 13 C labeling in acetate, acetylcarnitine, and citrate. V TCA was estimated to be 6.7 ± 1.7 μmol · g −1 · min −1 (dry weight), and was best estimated with a model using only the labeling in citrate and acetylcarnitine, independent of the precursor. The TCA cycle rate was not linear with the citrate-to-acetate metabolite ratio, and could thus not be quantified using a ratiometric approach. The 13 C signal evolution of citrate, i.e. citrate formation was independent of the amount of injected acetate, while the 13 C signal evolution of acetylcarnitine revealed a dose dependency with the injected acetate. The 13 C labeling of citrate did not correlate to that of acetylcarnitine, leading to the hypothesis that acetylcarnitine formation is not an indication of mitochondrial TCA cycle activity in the heart. Conclusions: Hyperpolarized [1-13 C]acetate is a metabolic probe independent of pyruvate dehydrogenase (PDH) activity. It allows the direct estimation of V TCA in vivo, which was shown to be neither dependent on the administered acetate dose nor on the 13 C labeling of acetylcarnitine. Dynamic 13 C MRS coupled to the injection of hyperpolarized [1-13 C]acetate can enable the measurement of metabolic changes during impaired heart function.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Direct noninvasive estimation of myocardial tricarboxylic acid cycle flux in vivo using hyperpolarized 13C magnetic resonance

Bastiaansen

Tian

Lei

et al. 2015

Journal of Molecular and Cellular Cardiology

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“…Propionyl--carnitine is particularly effective in promoting glucose oxidation at the expense of that of fatty acids, possibly because, in addition of the above effect of the carnitine moiety, the propionyl moiety generates oxaloacetate in the mitochondria, thus promoting the further utilization of intramitochondrial acetyl-CoA and increasing the rate of citrate formation (see [76]). The possibility that acetylcarnitine formation could lead to inhibition of CPTo through the formation of cytosolic malonyl-CoA [77] appears to have receded in view of the demonstration that cardiac muscle does not express a cytosolic carnitine acetyltransferase activity [78]. However, previous reports had indicated that an overt activity of the enzyme exists in the endoplasmic reticulum of the liver [79] ; it is not known whether an analogous overt activity exists in the sarcoplasmic reticulum.…”

Section: Cardiac Musclementioning

confidence: 99%

The malonyl-CoA–long-chain acyl-CoA axis in the maintenance of mammalian cell function

Zammit

1999

Biochemical Journal

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Long-chain acyl-CoA esters have potent specific actions (e.g. on gene transcription, membrane trafficking) as well as non-specific ones (e.g. on phospholipid bilayers). They are synthesized on the cytosolic aspects of several intracellular membranes, to give rise to (a) cytosolic pool(s) to which a variety of enzymes and processes have access, including some localized in the nucleus. Their concentration in cells is highly regulated, interconversion with corresponding acylcarnitines being the most important mechanism involved. This reaction is catalysed by cytosol-accessible carnitine long-chain acyl (palmitoyl) transferase activities that are themselves located on multiple membrane systems. Regulation of these activities is through the inhibitory action of malonyl-CoA. Hence the existence of a potent malonyl-CoA-acyl-CoA axis through which many processes involved in the maintenance of mammalian cell function are regulated. The molecular, topographical and physiological interactions that make this possible are described and discussed.

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“…It has been proposed that mitochondrial acetyl-CoA is transferred to the cytosol either via acetylcarnitine and the carnitine acetyl transferase system (14) or via citrate and ATP-citrate lyase (15,16). Arguing against the role of acetylcarnitine is the reported absence of extramitochondrial carnitine acetyl transferase in the heart (17). Although the activity of ATP-citrate lyase in the heart is low, it could sustain the rates of increase in malonyl-CoA concentration measured in perfused rat hearts following the addition of substrates that raise malonyl-CoA concentration (16).…”

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confidence: 99%

Peroxisomal Fatty Acid Oxidation Is a Substantial Source of the Acetyl Moiety of Malonyl-CoA in Rat Heart

Reszko

Kasumov

Jobbins

et al. 2004

Journal of Biological Chemistry

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Little is known about the sources of acetyl-CoA used for the synthesis of malonyl-CoA, a key regulator of mitochondrial fatty acid oxidation in the heart. In perfused rat hearts, we previously showed that malonylCoA is labeled from both carbohydrates and fatty acids. This study was aimed at assessing the mechanisms of incorporation of fatty acid carbons into malonyl-CoA. Rat hearts were perfused with glucose, lactate, pyruvate, and a fatty acid (palmitate, oleate or docosanoate). In each experiment, substrates were 13 C-labeled to yield singly or/and doubly labeled acetyl-CoA. The mass isotopomer distribution of malonyl-CoA was compared with that of the acetyl moiety of citrate, which reflects mitochondrial acetyl-CoA. In the presence of labeled glucose or lactate/pyruvate, the 13 C labeling of malonylCoA was up to 2-fold lower than that of mitochondrial acetyl-CoA. However, in the presence of a fatty acid labeled in its first acetyl moiety, the 13 C labeling of malonyl-CoA was up to 10-fold higher than that of mitochondrial acetyl-CoA. The labeling of malonyl-CoA and of the acetyl moiety of citrate is compatible with peroxisomal ␤-oxidation forming C 12 and C 14 acyl-CoAs and contributing >50% of the fatty acid-derived acetyl groups that end up in malonyl-CoA. This fraction increases with the fatty acid chain length. By supplying acetyl-CoA for malonyl-CoA synthesis, peroxisomal ␤-oxidation may participate in the control of mitochondrial fatty acid oxidation in the heart. In addition, this pathway may supply some acyl groups used in protein acylation, which is increasingly recognized as an important regulatory mechanism for many biochemical processes.Malonyl-CoA is an intermediate of fatty acid synthesis in lipogenic organs. It is also a key regulator of mitochondrial long-chain fatty acid oxidation in most mammalian tissues because it modulates the activity of carnitine palmitoyltransferase-I (1-4). Malonyl-CoA is formed by cytosolic acetyl-CoA carboxylase (ACC) 1 and is disposed off either by lipogenesis or via malonyl-CoA decarboxylase, which reforms acetyl-CoA. Alterations in malonyl-CoA metabolism and regulation have been associated with insulin resistance and obesity (5). Mice lacking ACC␤, the predominant ACC isoform in cardiac and skeletal muscle, show not only decreased malonyl-CoA levels and increased fatty acid oxidation but also major alterations in systemic energy balance with decreased body fat despite increased food intake (6). The above data emphasize the crucial role of malonyl-CoA in fat metabolism and energy balance. In the heart, much work has been conducted on the control of malonyl-CoA metabolism, emphasizing the mechanisms of regulation of ACC␤ and malonyl-CoA decarboxylase. This includes acute changes in activity through phosphorylation via cAMPdependent protein kinase or AMP kinase (for recent reviews, see Refs. 5 and 7-10), as well as chronic regulation through gene expression involving peroxisomal proliferator-activated receptor (11,12). However, little is known about the origin of ac...

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Carnitine Acetyltransferase is not a Cytosolic Enzyme in Rat Heart and Therefore Cannot Function in the Energy-linked Regulation of Cardiac Fatty Acid Oxidation

Cited by 26 publications

References 4 publications

Direct noninvasive estimation of myocardial tricarboxylic acid cycle flux in vivo using hyperpolarized 13C magnetic resonance

Direct noninvasive estimation of myocardial tricarboxylic acid cycle flux in vivo using hyperpolarized 13C magnetic resonance

The malonyl-CoA–long-chain acyl-CoA axis in the maintenance of mammalian cell function

Peroxisomal Fatty Acid Oxidation Is a Substantial Source of the Acetyl Moiety of Malonyl-CoA in Rat Heart

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