Arduini, Arduino

Zammit, Victor A.

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Victor Zammit

Arduino Arduini

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Acetate trafficking in the heart: carnitine acyltransferases matter

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     warwick.ac.uk/lib-publications      Original citation: Zammit, Victor A. and Arduini, Arduino. (2016) Acetate trafficking in the heart : carnitine acyltransferases matter. Physiological Reports, 4 (19). e12997.  Permanent WRAP URL: http://wrap.warwick.ac.uk/85225                         Copyright and reuse: The Warwick Research Archive Portal (WRAP) makes this work of researchers of the University of Warwick available open access under the following conditions.  This article is made available under the Creative Commons Attribution 4.0 International license (CC BY 4.0) and may be reused according to the conditions of the license.  For more details see: http://creativecommons.org/licenses/by/4.0/    A note on versions: The version presented in WRAP is the published version, or, version of record, and may be cited as it appears here.  For more information, please contact the WRAP Team at: wrap@warwick.ac.uk  LETTER TO THE EDITORAcetate trafficking in the heart: carnitine acyltransferasesmatterVictor Zammit1 & Arduino Arduini21 Translational Medicine, Warwick Medical School, University of Warwick, Coventry, UK2 R&D Department, CoreQuest Sagl, Manno, SwitzerlandE-mail: v.a.zammit@warwick.ac.ukdoi: 10.14814/phy2.12997Dear Editor,The use of hyperpolarized 13C magnetic resonance tostudy intermediary metabolism is increasing rapidly, sinceit allows in vivo noninvasive investigation of dynamicmetabolic and physiological processes that were previ-ously experimentally inaccessible. A recent study pub-lished in the Journal by Koellish and colleagues used thetechnique to address the fate of hyperpolarized 13C-labeled acetate in STZ-induced diabetic rats (Koellischet al. 2015a). While the use of this advanced technologyis welcome, a basic misinterpretation of the cellular meta-bolic fate of acetate is apparent in the paper (Koellischet al. 2015a). In particular, the authors have seriouslymisrepresented the mechanism of transfer of the acetatemoiety across the mitochondrial inner membrane, confus-ing it with the one utilized by long-chain fatty acids, inwhich the carnitine palmitoyltransferases (CPT1 andCPT2) and the inner membrane carrier carnitine acylcar-nitine translocase (CACT) are crucial (Zammit 1999). Inaddition, because of this error, the authors state that car-nitine acetyltransferase (termed CAT1 by the authors) issensitive to malonyl-CoA inhibition. This is not tenable,as malonyl-CoA inhibition relates solely to carnitinepalmitoyltransferases (CPT1A, CPT1B), and not to car-nitine acetyltransferase. This basic misunderstanding ofacetate metabolism is also apparent in previous workpublished by these authors (Koellisch et al. 2015b).Carnitine acetyltransferase (generally referred to asCRAT or CAT) has mitochondrial and peroxisomal iso-forms (which are not referred to as 1 or 2) and are notmalonyl-CoA sensitive. The formation of the latter is adiversion of acetyl-CoA formed by b-oxidation of fattyacids (and other cellular fuels) from oxidation in the tri-carboxylic acid cycle (Zammit et al. 2009). The pathway:acetate ? acetyl-CoA ? acetylcarnitine cannot be equa-ted with the “rate of fatty acid oxidation”, especially whenartificially high levels of acetate are imposed experimen-tally. The formation of acetylcarnitine has an importantpart to play in the regulation of intramitochondrialacetyl-CoA levels, and, therefore, the balance between glu-cose and fatty acid utilization by tissues (Zammit et al.2009). But, rationalization of this role requires knowledgeof the identity, properties and roles of the different mem-bers of the carnitine acyltransferase family of enzymes,and specifically, an appropriate distinction between thosethat catalyze the utilization of carnitine esters with differ-ent acyl chain lengths.In addition, it is noteworthy that parenteral administra-tion of very high acetate dosages, as used by Koellish et al.,can be calculated to lead to a plasma exposure of approxi-mately 10 mmol/L, whereas physiological acetate levels areusually very much lower in the plasma of mammals(<0.1 mmol/L) (Veech 1988). Therefore, the protocol usedmay have significantly, and nonphysiologically, perturbedthe cellular, and particularly, the intramitochondrialacetyl-CoA pool (Taegtmeyer et al. 1980). Furthermore,the severity of the diabetic state induced by the experimen-tal model (streptozotocin injection) appears to have beenvery variable, as the reported blood glucose levels rangedfrom 10 to 30 mmol/L (Koellisch et al. 2015a). Assumingthat glycemic levels were obtained in fasted animals (notstated in the manuscript) such variability may furtherhamper the interpretation of the tracer data obtained.ReferencesKoellisch, U., C. Laustsen, T. S. Nørlinger, J. A. Østergaard, A.Flyvbjerg, C. V. Gringeri, et al. 2015a. Investigation ofmetabolic changes in STZ-induced diabetic rats withhyperpolarized [1-13C]acetate. Physiol. Rep. 3:e12474. doi:10.14814/phy2.12474.Koellisch, U., C. V. Gringeri, G. Rancan, E. V. Farell, M. I.Menzel, A. Haase, et al. 2015b. Metabolic imaging ofhyperpolarized [1-13C]acetate and [1-13C]acetylcarnitine -investigation of the influence of dobutamine induced stress.Magn. Reson. Med. 74:1011–1018.Taegtmeyer, H., R. Hems, and H. A. Krebs. 1980. Utilizationof energy-providing substrates in the isolated working ratheart. Biochem. J. 186:701–711.ª 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf ofthe American Physiological Society and The Physiological Society.This is an open access article under the terms of the Creative Commons Attribution License,which permits use, distribution and reproduction in any medium, provided the original work is properly cited.2016 | Vol. 4 | Iss. 19 | e12997Page 1Physiological Reports ISSN 2051-817XVeech, R. L. 1988. The untoward effects of the anions ofdialysis fluids. Kidney Int. 34:587–597.Zammit, V. A. 1999. Carnitine acyltransferases: functionalsignificance of subcellular distribution and membranetopology. Prog. Lipid Res. 38:199–224.Zammit, V. A., R. R. Ramsay, M. Bonomini, and A. Arduini.2009. Carnitine, mitochondrial function and therapy. Adv.Drug Deliv. Rev. 61:1353–1362.2016 | Vol. 4 | Iss. 19 | e12997Page 2ª 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf ofthe American Physiological Society and The Physiological Society.Letter to the Editor

Acetate trafficking in the heart : carnitine acyltransferases matter

Acetate trafficking in the heart : carnitine acyltransferases matter

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