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

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 malonyl-CoA 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 13C-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 13C labeling of malonyl-CoA 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 13C 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 β-oxidation forming C12 and C14 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 β-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. 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 malonyl-CoA 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 13C-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 13C labeling of malonyl-CoA 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 13C 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 β-oxidation forming C12 and C14 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 β-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 (1McGarry J.D. Mills S.E. Long C.S. Foster D.W. Biochem. J. 1983; 214: 21-28Crossref PubMed Scopus (462) Google Scholar, 2McGarry J.D. Leatherman G.F. Foster D.W. J. Biol. Chem. 1978; 253: 4128-4136Abstract Full Text PDF PubMed Google Scholar, 3Robinson I.N. Zammit V.A. Biochem. J. 1982; 206: 177-179Crossref PubMed Scopus (57) Google Scholar, 4Chien D. Dean D. Saha A.K. Flatt J.P. Ruderman N.B. Am. J. Physiol. 2000; 279: E259-E265Crossref PubMed Google Scholar). Malonyl-CoA is formed by cytosolic acetyl-CoA carboxylase (ACC) 1The abbreviations used are: ACC, acetyl-CoA carboxylase, MPE, molar percent enrichment. 1The abbreviations used are: ACC, acetyl-CoA carboxylase, MPE, molar percent enrichment. 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 (5Ruderman N.B. Saha A.K. Vavvas D. Witters L.A. Am. J. Physiol. 1999; 276: E1-E18Crossref PubMed Google Scholar). Mice lacking ACCβ, 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 (6Abu-Elheiga L. Matzuk M.M. Abo-Hashema K.A. Wakil S.J. Science. 2001; 291: 2613-2616Crossref PubMed Scopus (733) Google Scholar). 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 ACCβ and malonyl-CoA decarboxylase. This includes acute changes in activity through phosphorylation via cAMP-dependent protein kinase or AMP kinase (for recent reviews, see Refs. 5Ruderman N.B. Saha A.K. Vavvas D. Witters L.A. Am. J. Physiol. 1999; 276: E1-E18Crossref PubMed Google Scholar and 7Zammit V.A. Biochem. J. 1999; 343: 505-515Crossref PubMed Scopus (99) Google Scholar, 8Saddik M. Gamble J. Witters L.A. Lopaschuk G.D. J. Biol. Chem. 1993; 268: 25836-25845Abstract Full Text PDF PubMed Google Scholar, 9Dyck J.R. Berthiaume L.G. Thomas P.D. Kantor P.F. Barr A.J. Barr R. Singh D. Hopkins T.A. Voilley N. Prentki M. Lopaschuk G.D. Biochem. J. 2000; 350: 599-608Crossref PubMed Scopus (60) Google Scholar, 10Longnus S.L. Wambolt R.B. Barr R.L. Lopaschuk G.D. Allard M.F. Am. J. Physiol. 2001; 281: H1561-H1567PubMed Google Scholar), as well as chronic regulation through gene expression involving peroxisomal proliferator-activated receptor (11Campbell F.M. Kozak R. Wagner A. Altarejos J.Y. Dyck J.R. Belke D.D. Severson D.L. Kelly D.P. Lopaschuk G.D. J. Biol. Chem. 2002; 277: 4098-4103Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar, 12Young M.E. Goodwin G.W. Ying J. Guthrie P. Wilson C.R. Laws F.A. Taegtmeyer H. Am. J. Physiol. 2001; 280: E471-E479Crossref PubMed Google Scholar). However, little is known about the origin of acetyl-CoA used for malonyl-CoA synthesis. Acetyl-CoA is produced predominantly in the mitochondria. The concentration of acetyl-CoA available to cytosolic ACCβ appears to be in the low μm range (13Robishaw J.D. Neely J.R. Am. J. Physiol. 1985; 248: E1-E9Crossref PubMed Google Scholar), i.e. much below the Km of ACCβ for acetyl-CoA. It has been proposed that mitochondrial acetyl-CoA is transferred to the cytosol either via acetylcarnitine and the carnitine acetyl transferase system (14Lopaschuk G.D. Gamble J. Can. J. Physiol. Pharmacol. 1994; 72: 1101-1109Crossref PubMed Scopus (76) Google Scholar) or via citrate and ATP-citrate lyase (15Saha A.K. Vavvas D. Kurowski T.G. Apazidis A. Witters L.A. Shafrir E. Ruderman N.B. Am. J. Physiol. 1997; 272: E641-E648PubMed Google Scholar, 16Poirier M. Vincent G. Reszko A.E. Bouchard B. Kelleher J.K. Brunengraber H. Des Rosiers C. Am. J. Physiol. 2002; 283: H1379-H1386Crossref PubMed Scopus (30) Google Scholar). Arguing against the role of acetylcarnitine is the reported absence of extramitochondrial carnitine acetyl transferase in the heart (17Abbas A.S. Wu G. Schulz H. J. Mol. Cell. Cardiol. 1998; 30: 1305-1309Abstract Full Text PDF PubMed Scopus (24) Google Scholar). 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 (16Poirier M. Vincent G. Reszko A.E. Bouchard B. Kelleher J.K. Brunengraber H. Des Rosiers C. Am. J. Physiol. 2002; 283: H1379-H1386Crossref PubMed Scopus (30) Google Scholar). Also, the physiological release of citrate by the heart (18Comte B. Vincent G. Bouchard B. Des Rosiers C. J. Biol. Chem. 1997; 272: 26117-26124Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 19Vincent G. Comte B. Poirier M. Des Rosiers C. Am. J. Physiol. 2000; 278: E846-E856Crossref PubMed Google Scholar) implies that citrate is available to cytosolic ATP-citrate lyase after transport from the mitochondria (20Cheema-Dhadli S. Robinson B.H. Halperin M.L. Can. J. Biochem. 1976; 54: 561-565Crossref PubMed Scopus (18) Google Scholar). Using a new gas chromatography-mass spectrometry technique (21Reszko A.E. Kasumov T. Comte B. Pierce B.A. David F. Bederman I.R. Deutsch J. Des Rosiers C. Brunengraber H. Anal. Biochem. 2001; 298: 69-75Crossref PubMed Scopus (41) Google Scholar), we showed that [13C]oleate contributes carbon to the acetyl moiety of malonyl-CoA (16Poirier M. Vincent G. Reszko A.E. Bouchard B. Kelleher J.K. Brunengraber H. Des Rosiers C. Am. J. Physiol. 2002; 283: H1379-H1386Crossref PubMed Scopus (30) Google Scholar). Also, experiments with hydroxycitrate, an inhibitor of ATP-citrate lyase (22Watson J.A. Fang M. Lowenstein J.M. Arch. Biochem. Biophys. 1969; 135: 209-217Crossref PubMed Scopus (207) Google Scholar), support an at least partial role of citrate as a precursor of the acetyl moiety of malonyl-CoA in the heart (16Poirier M. Vincent G. Reszko A.E. Bouchard B. Kelleher J.K. Brunengraber H. Des Rosiers C. Am. J. Physiol. 2002; 283: H1379-H1386Crossref PubMed Scopus (30) Google Scholar) and in muscle (15Saha A.K. Vavvas D. Kurowski T.G. Apazidis A. Witters L.A. Shafrir E. Ruderman N.B. Am. J. Physiol. 1997; 272: E641-E648PubMed Google Scholar). The present study was undertaken to characterize the contributions of glucose, lactate/pyruvate, and fatty acids of different chain length to the acetyl moiety of malonyl-CoA in rat hearts perfused under conditions that mimic the in vivo milieu, in terms of substrate supply to the heart. We used mass isotopomer 2Mass isotopomers are designated as Mn, where n is the number of atomic mass units above the molecular weight of the unlabeled isotopomer M. 2Mass isotopomers are designated as Mn, where n is the number of atomic mass units above the molecular weight of the unlabeled isotopomer M. analysis (23Brunengraber H. Kelleher J.K. Des Rosiers C. Annu. Rev. Nutr. 1997; 17: 559-596Crossref PubMed Scopus (94) Google Scholar) to compare the labeling patterns of malonyl-CoA and of the acetyl moiety of citrate labeled from various 13C-labeled substrates. Our strategy was to use combinations of labeled substrates that generate M2 and M1 mitochondrial acetyl-CoA, for example, [U-13C3](lactate + pyruvate) and [1-13C]oleate, respectively. Our data clearly demonstrate the participation of peroxisomal β-oxidation (24Lazarow P.B. De Duve C. Proc. Natl. Acad. Sci. U. S. A. 1976; 73: 2043-2046Crossref PubMed Scopus (1171) Google Scholar, 25Reddy J.K. Mannaerts G.P. Annu. Rev. Nutr. 1994; 14: 343-370Crossref PubMed Scopus (361) Google Scholar, 26Mannaerts G.P. Van M. Biochem. Biophys. 2000; PubMed Scopus Google Scholar) to the supply of acetyl-CoA to malonyl-CoA and were from and acid were from acid was from of was and by (21Reszko A.E. Kasumov T. Comte B. Pierce B.A. David F. Bederman I.R. Deutsch J. Des Rosiers C. Brunengraber H. Anal. Biochem. 2001; 298: 69-75Crossref PubMed Scopus (41) Google Scholar). acid was M. David F. Brunengraber H. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar) from and and ATP-citrate lyase was J. Biol. Chem. Full Text PDF PubMed Google Scholar) from the of that been for and for with a glucose The from the J. Biol. Chem. Full Text PDF PubMed Google Scholar), was with and of the were at the was in of were for with from were perfused in the with fatty μm and physiological of carbohydrates lactate, and pyruvate) and a fatty acid or to mimic the in vivo conditions G. Bouchard B. M. Des Rosiers C. Am. J. Physiol. PubMed Scopus Google Scholar) of unlabeled and labeled substrates lactate, pyruvate, were to a range of 13C of malonyl-CoA and of the acetyl moiety of citrate experiments by a with substrates on the unlabeled substrates were by the labeled in isotopomer analysis to use of labeled substrates in the which generate M1 and M2 mass isotopomers of both malonyl-CoA and the acetyl moiety of and were used both unlabeled and The hearts were after of with the labeled of of rat of + + in a new concentration and 13C labeling of malonyl-CoA were as previously (21Reszko A.E. Kasumov T. Comte B. Pierce B.A. David F. Bederman I.R. Deutsch J. Des Rosiers C. Brunengraber H. Anal. Biochem. 2001; 298: 69-75Crossref PubMed Scopus (41) Google Scholar). We a technique for the mass isotopomer distribution of the acetyl moiety of of heart was with of The acid was with to and the was at and at to of acetyl-CoA. the the was with and with and The was with units of ATP-citrate The of the was by the in at the was at the was through an with of by of the the was with of in and acetyl-CoA was with of in a the was in of and by chromatography-mass The were The mass isotopomer distribution of of acid and of M2 and M1 acetyl-CoA was by gas chromatography-mass spectrometry of citrate formed by the acid with and are as molar percent as previously (18Comte B. Vincent G. Bouchard B. Des Rosiers C. J. Biol. Chem. 1997; 272: 26117-26124Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, G. Bouchard B. M. Des Rosiers C. Am. J. Physiol. PubMed Scopus Google Scholar). mass isotopomers of to n 13C are as with and the of 13C-labeled mass isotopomers of a was as where and the from for to unlabeled and 13C-labeled mass respectively. We present data from about heart each of the conditions we in the presence of 13C-labeled with the to in are the M2 and M1 13C of malonyl-CoA or acetyl moiety of citrate measured in a heart of gas chromatography-mass spectrometry or chromatography-mass spectrometry which by The of the 13C of malonyl-CoA and of the acetyl moiety of citrate for the conducted for various under a was a The 13C moiety of with a 13C-labeled substrate in a are reported as S.E. of n with the first of hearts were perfused with glucose, lactate, pyruvate, and oleate 13C we used + pyruvate) or In the M2 and M1 of malonyl-CoA the of and oleate to the acetyl moiety of malonyl-CoA. to the labeling of the acetyl moiety of citrate, which reflects mitochondrial acetyl-CoA. this and the of labeling of malonyl-CoA and the acetyl moiety of citrate are in The M1 and M2 labeling moiety of are in the of 2Mass isotopomer of malonyl-CoA and of the acetyl moiety of citrate in hearts perfused with isotopomer of malonyl-CoA and the acetyl moiety of citrate in hearts perfused with or with + + pyruvate) and isotopomer of malonyl-CoA and the acetyl moiety of citrate in hearts perfused with + The M2 of malonyl-CoA from [U-13C3](lactate + pyruvate) and from a low of carbohydrates to malonyl-CoA. In the M1 of malonyl-CoA from increased and about after This was in the presence of [1-13C]oleate, the M1 of mitochondrial acetyl-CoA is from glucose and to acetyl-CoA. the acetyl moiety of malonyl-CoA could not be from mitochondrial acetyl-CoA. the M1 of the acetyl moiety of citrate at to mitochondrial acetyl-CoA. However, the M1 of the acetyl moiety of citrate was about that of malonyl-CoA In the M2 of the acetyl moiety of citrate from [U-13C3](lactate + pyruvate) or at a that was 2-fold than that of malonyl-CoA and The data of and show that the contributions of pyruvate, and glucose to mitochondrial acetyl-CoA, and up to to which with (16Poirier M. Vincent G. Reszko A.E. Bouchard B. Kelleher J.K. Brunengraber H. Des Rosiers C. Am. J. Physiol. 2002; 283: H1379-H1386Crossref PubMed Scopus (30) Google Scholar, 19Vincent G. Comte B. Poirier M. Des Rosiers C. Am. J. Physiol. 2000; 278: E846-E856Crossref PubMed Google Scholar), that is little of substrates to mitochondrial acetyl-CoA. the data of and demonstrate that some of the malonyl-CoA from not from the mitochondrial metabolism of this this we that the M1 of malonyl-CoA was at least in from the partial peroxisomal β-oxidation of [1-13C]oleate, forming in the of with support for a of peroxisomal β-oxidation of fatty acids to malonyl-CoA we used is a long-chain fatty acid that is in J.K. Mannaerts G.P. Annu. Rev. Nutr. 1994; 14: 343-370Crossref PubMed Scopus (361) Google Scholar). of its low in the presence of we perfused rat hearts with only the M2 labeling of malonyl-CoA, which at about In the M2 of the acetyl moiety of citrate at only about only of the acetyl units of were mitochondrial oxidation of the substrate have in a M2 of the acetyl moiety of citrate of In the presence of the 10-fold in the M2 of malonyl-CoA and acetyl moiety of citrate that most of the acetyl moiety of malonyl-CoA is from peroxisomal with the experiments reported in the above the fatty acids oleate and were 13C-labeled on the first not the of the acetyl-CoA only in mitochondria. The of 13C-labeled or to the of the various acetyl groups of of hearts were perfused with glucose, lactate, pyruvate, and first the groups of conducted with + unlabeled and with + + pyruvate) + unlabeled in the M2 of malonyl-CoA labeled from increased to at In the the M2 of the acetyl moiety of citrate at at was the of to mitochondrial acetyl-CoA at In experiments with + + pyruvate) + unlabeled the M2 and M1 of malonyl-CoA at and of mitochondrial acetyl-CoA at and in the experiments with the contributions of lactate/pyruvate, and glucose to mitochondrial acetyl-CoA up to to little from of was conducted under the conditions with a of and 13C substrates in the the of the and the first acetyl groups of as M1 and M2 respectively. were perfused with + each in the M1 of malonyl-CoA was 10-fold lower than its M2 enrichment. In the M1 of the acetyl moiety of citrate was 2-fold lower than its M2 enrichment. data for a metabolism of the and acetyl groups of to the acetyl-CoA used by heart cytosolic acetyl-CoA carboxylase to malonyl-CoA is of mitochondrial origin and is transferred from the mitochondria via acetylcarnitine (14Lopaschuk G.D. Gamble J. Can. J. Physiol. Pharmacol. 1994; 72: 1101-1109Crossref PubMed Scopus (76) Google Scholar) or via citrate and ATP-citrate lyase (15Saha A.K. Vavvas D. Kurowski T.G. Apazidis A. Witters L.A. Shafrir E. Ruderman N.B. Am. J. Physiol. 1997; 272: E641-E648PubMed Google Scholar, 16Poirier M. Vincent G. Reszko A.E. Bouchard B. Kelleher J.K. Brunengraber H. Des Rosiers C. Am. J. Physiol. 2002; 283: H1379-H1386Crossref PubMed Scopus (30) Google Scholar). The major of this study is the that a of malonyl-CoA is from acetyl-CoA from extramitochondrial long-chain chain fatty acid This was by the 13C labeling of malonyl-CoA with that of the acetyl moiety of citrate, which reflects mitochondrial acetyl-CoA. In the presence of fatty acids labeled in the first acetyl moiety, the labeling of was than In in the presence of labeled glucose or lactate/pyruvate, the labeling of was than In hearts perfused with [U-13C3](lactate + pyruvate) and [1-13C]oleate, the M2 of malonyl-CoA [U-13C3](lactate + at about that of mitochondrial acetyl-CoA This implies that the labeling of M2 acetyl-CoA transferred from mitochondria was by unlabeled acetyl-CoA formed in the extramitochondrial The only known of unlabeled extramitochondrial acetyl-CoA the absence of is the partial peroxisomal oxidation of fatty acids. Although was in its first its oxidation not generate M2 acetyl-CoA. acetyl-CoA from the partial peroxisomal oxidation of are and the M2 labeling of acetyl-CoA from [U-13C3](lactate + In the M1 of malonyl-CoA labeled from was that of mitochondrial acetyl-CoA. The only be by the of M1 acetyl-CoA through extramitochondrial oxidation of [1-13C]oleate, most in In it appears under the conditions of about of the extramitochondrial acetyl-CoA used to malonyl-CoA was from the and was from extramitochondrial β-oxidation of fatty acids. the M2 of mitochondrial acetyl-CoA from [U-13C3](lactate + pyruvate) was 2-fold after its to the extramitochondrial we that a 2-fold to the M1 of mitochondrial acetyl-CoA from to we the M1 of extramitochondrial acetyl-CoA from the peroxisomal β-oxidation of of of malonyl-CoA, were from acetyl-CoA at and were from acetyl-CoA at a a of acetyl-CoA from the peroxisomal β-oxidation of in from peroxisomal β-oxidation was it appears that of peroxisomal on This that the was the of peroxisomal β-oxidation in Our data are compatible with on partial peroxisomal β-oxidation of long-chain acyl-CoAs G.P. Van M. Biochem. Biophys. 2000; PubMed Scopus Google Scholar). was in to an unlabeled C12 which either was transferred to the mitochondria for oxidation or could be in the of heart Mol. Biochem. 2002; PubMed Scopus Google Scholar). for the participation of an extramitochondrial β-oxidation pathway to the of acetyl-CoA for malonyl-CoA synthesis from experiments with this the extramitochondrial acetyl-CoA were to be from the have of peroxisomal β-oxidation to acetyl-CoA and unlabeled The presence of some labeling of mitochondrial acetyl-CoA from the from the extramitochondrial to the mitochondrial of or of from the by of peroxisomal via the carnitine system or from partial peroxisomal β-oxidation of via the carnitine The first mechanism is compatible with the presence of a long-chain and a long-chain in mitochondria T. S. T. J. Biol. Chem. Full Text PDF PubMed Google Scholar, T. T. J. Biol. Chem. Full Text PDF PubMed Google Scholar). In a of experiments an of labeled in the first or acetyl units into the mechanisms in the extramitochondrial of acetyl-CoA. The M1 of malonyl-CoA was lower than its M2 enrichment. This was malonyl-CoA only via labeling of mitochondrial acetyl-CoA, malonyl-CoA via mitochondrial acetyl-CoA and peroxisomal the mass isotopomer of the acetyl moiety of citrate and of malonyl-CoA in hearts that the M2 of malonyl-CoA, from is higher than the M2 of the acetyl moiety of some of the M2 labeling of malonyl-CoA was from partial peroxisomal β-oxidation of Also, the M1 of malonyl-CoA, from is lower than the M1 of the acetyl moiety of This from the of unlabeled acetyl-CoA by partial peroxisomal β-oxidation of The of of of acetyl moiety of is because of the low M1 of malonyl-CoA. the at about the for the experiments with [1-13C]oleate, that the labeled substrate through or of peroxisomal This is compatible with the of and Van Biophys. PubMed Scopus Google Scholar), from of rat heart with in the presence of and The of the in the M1 and M2 of malonyl-CoA is by the that the M2 labeling of the acetyl moiety of citrate from was about that of its M1 labeling from could have that the the acetyl moiety of This be by the following The of from to mitochondrial acetyl-CoA is only partial because of the of the of the mitochondrial C. Physiol. Chem. PubMed Scopus Google Scholar, G. S. Des Rosiers C. M. David F. T. Brunengraber H. J. Biol. Chem. Full Text PDF PubMed Google Scholar) and the of the mitochondrial transferase that to G. Comte B. Poirier M. Des Rosiers C. Am. J. Physiol. 2000; 278: E846-E856Crossref PubMed Google Scholar, G. S. Des Rosiers C. M. David F. T. Brunengraber H. J. Biol. Chem. Full Text PDF PubMed Google Scholar). In the the of the + acetyl of with the acetyl-CoA is much than the of the + acetyl C. Physiol. Chem. PubMed Scopus Google Scholar). This was also in for the mitochondrial C. Physiol. Chem. PubMed Scopus Google Scholar, S. J.M. A. S. J. Biol. Chem. 1982; Full Text PDF PubMed Google Scholar, Des Rosiers C. Brunengraber H. Arch. Biochem. Biophys. PubMed Scopus Google Scholar) and cytosolic G. J. Brunengraber H. J. Biol. Chem. 1982; Full Text PDF PubMed Google Scholar). from the carbons of is labeled in its + acetyl compared with its + the transferase the labeled is to labeled which is in the G. S. Des Rosiers C. M. David F. T. Brunengraber H. J. Biol. Chem. Full Text PDF PubMed Google Scholar). a the mitochondrial acetyl-CoA is labeled is labeled in its first acetyl are of the of peroxisomal oxidation to the of long-chain fatty acid oxidation in the heart J.K. Mannaerts G.P. Annu. Rev. Nutr. 1994; 14: 343-370Crossref PubMed Scopus (361) Google Scholar). However, data from this the range of the of peroxisomal oxidation to sustain the of malonyl-CoA. The of rat heart malonyl-CoA is about of (21Reszko A.E. Kasumov T. Comte B. Pierce B.A. David F. Bederman I.R. Deutsch J. Des Rosiers C. Brunengraber H. Anal. Biochem. 2001; 298: 69-75Crossref PubMed Scopus (41) Google Scholar). peroxisomal oxidation contributes at least of the acetyl-CoA used for malonyl-CoA synthesis, the could be by a of peroxisomal oxidation of about of This is lower than the of acetyl-CoA produced from mitochondrial β-oxidation of long-chain fatty acids in hearts perfused with a of substrates oleate G. Comte B. Poirier M. Des Rosiers C. Am. J. Physiol. 2000; 278: E846-E856Crossref PubMed Google Scholar). a low of peroxisomal fatty acid oxidation is to sustain the of heart malonyl-CoA. However, acetyl-CoA formed by peroxisomal fatty acid oxidation also be used in Also, the C12 and C14 acyl-CoAs from peroxisomal β-oxidation be used in protein acylation, which is increasingly recognized as an important regulatory mechanism for many biochemical Mol. Biochem. 2002; PubMed Scopus Google Scholar, T.G. 1999; PubMed Scopus Google Scholar). the heart is not a lipogenic the C12 and C14 acyl-CoAs could be from the partial peroxisomal oxidation of long-chain fatty acids. In data from this study conducted in hearts perfused with a substrate the in show that a fraction of the fatty acid carbon into malonyl-CoA is from peroxisomal β-oxidation and that this fraction increases with the fatty acid chain length. Also, the labeling of malonyl-CoA as a of peroxisomal it appears that and are in to The could be in mitochondria could participate in protein Mol. Biochem. 2002; PubMed Scopus Google Scholar). the concentration of cytosolic acetyl-CoA is much lower than the Km of acetyl-CoA carboxylase for acetyl-CoA, the supply of cytosolic acetyl-CoA be a of the regulation of malonyl-CoA peroxisomal which acetyl-CoA to the cytosolic of acetyl-CoA carboxylase, may to the regulation of malonyl-CoA metabolism and of mitochondrial fatty acid the of fatty acid on the of peroxisomal β-oxidation to the acetyl moiety of malonyl-CoA and the of under conditions where through peroxisomal proliferator-activated receptor is as M. F. J.M. A. Kelly D.P. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). We and for with the and heart

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