Acyl-CoA thioesterase-2 facilitates mitochondrial fatty acid oxidation in the liver

Abstract

Acyl-CoA thioesterase (Acot)2 localizes to the mitochondrial matrix and hydrolyses long-chain fatty acyl-CoA into free FA and CoASH. Acot2 is expressed in highly oxi­dative tissues and is poised to modulate mitochondrial FA oxidation (FAO), yet its biological role is unknown. Using a model of adenoviral Acot2 overexpression in mouse liver (Ad-Acot2), we show that Acot2 increases the utilization of FA substrate during the daytime in ad libitum-fed mice, but the nighttime switch to carbohydrate oxidation is similar to control mice. In further support of elevated FAO in Acot2 liver, daytime serum ketones were higher in Ad-Acot2 mice, and overnight fasting led to minimal hepatic steatosis as compared with control mice. In liver mitochondria from Ad-Acot2 mice, phosphorylating O2 consumption was higher with lipid substrate, but not with nonlipid substrate. This increase depended on whether FA could be activated on the outer mitochondrial membrane, suggesting that the FA released by Acot2 could be effluxed from mitochondria then taken back up again for oxidation. This circuit would prevent the build-up of inhibitory long-chain fatty acyl-CoA esters. Altogether, our findings indicate that Acot2 can enhance FAO, possibly by mitigating the accumulation of FAO intermediates within the mitochondrial matrix. Acyl-CoA thioesterase (Acot)2 localizes to the mitochondrial matrix and hydrolyses long-chain fatty acyl-CoA into free FA and CoASH. Acot2 is expressed in highly oxi­dative tissues and is poised to modulate mitochondrial FA oxidation (FAO), yet its biological role is unknown. Using a model of adenoviral Acot2 overexpression in mouse liver (Ad-Acot2), we show that Acot2 increases the utilization of FA substrate during the daytime in ad libitum-fed mice, but the nighttime switch to carbohydrate oxidation is similar to control mice. In further support of elevated FAO in Acot2 liver, daytime serum ketones were higher in Ad-Acot2 mice, and overnight fasting led to minimal hepatic steatosis as compared with control mice. In liver mitochondria from Ad-Acot2 mice, phosphorylating O2 consumption was higher with lipid substrate, but not with nonlipid substrate. This increase depended on whether FA could be activated on the outer mitochondrial membrane, suggesting that the FA released by Acot2 could be effluxed from mitochondria then taken back up again for oxidation. This circuit would prevent the build-up of inhibitory long-chain fatty acyl-CoA esters. Altogether, our findings indicate that Acot2 can enhance FAO, possibly by mitigating the accumulation of FAO intermediates within the mitochondrial matrix. Pathophysiological mechanisms that underlie metabolic dysfunction such as insulin resistance and nonalcoholic fatty liver disease are complex. A role for mitochondrial FA oxidation (FAO) as a driver of dysfunction has been postulated (1Koves T.R. Ussher J.R. Noland R.C. Slentz D. Mosedale M. Ilkayeva O. Bain J. Stevens R. Dyck J.R. Newgard C.B. et al.Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance.Cell Metab. 2008; 7: 45-56Abstract Full Text Full Text PDF PubMed Scopus (1409) Google Scholar, 2Muoio D.M. Neufer P.D. Lipid-induced mitochondrial stress and insulin action in muscle.Cell Metab. 2012; 15: 595-605Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar, 3Muoio D.M. Noland R.C. Kovalik J.P. Seiler S.E. Davies M.N. DeBalsi K.L. Ilkayeva O.R. Stevens R.D. Kheterpal I. Zhang J. et al.Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility.Cell Metab. 2012; 15: 764-777Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar), yet the mechanistic link between cellular metabolic dysfunction and mitochondrial FAO remains poorly defined (2Muoio D.M. Neufer P.D. Lipid-induced mitochondrial stress and insulin action in muscle.Cell Metab. 2012; 15: 595-605Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar). Insight would be gained by a better understanding of FAO. In particular, the modulation of β-oxidation substrates and intermediates by mechanisms within the mitochondria is poorly understood, but is of interest in the context of evidence suggesting that long-chain fatty acyl-CoA esters can inhibit FAO (4van Eunen K. Simons S.M. Gerding A. Bleeker A. den Besten G. Touw C.M. Houten S.M. Groen B.K. Krab K. Reijngoud D.J. et al.Biochemical competition makes fatty-acid beta-oxidation vulnerable to substrate overload.PLOS Comput. Biol. 2013; 9: e1003186Crossref PubMed Scopus (41) Google Scholar, 5Shug A. Lerner E. Elson C. Shrago E. The inhibition of adenine nucleotide translocase activity by oleoyl CoA and its reversal in rat liver mitochondria.Biochem. Biophys. Res. Commun. 1971; 43: 557-563Crossref PubMed Scopus (137) Google Scholar, 6Woldegiorgis G. Yousufzai S.Y. Shrago E. Studies on the interaction of palmitoyl coenzyme A with the adenine nucleotide translocase.J. Biol. Chem. 1982; 257: 14783-14787Abstract Full Text PDF PubMed Google Scholar). Acyl-CoA thioesterases (Acots) in mitochondria, by virtue of their major substrates (long-chain fatty acyl-CoAs) and hydrolase activity which generates FA anion and free CoASH, have the potential to modulate the levels of FAO substrates and intermediates, and consequently to modulate FAO. The Acots are classified as type I or II based on catalytic domain structure, and localize to the cytosol, peroxisomes, and mitochondria. The mitochondrial Acots are Acot2 (mitochondrial matrix) (7Hunt M.C. Solaas K. Kase B.F. Alexson S.E. Characterization of an acyl-coA thioesterase that functions as a major regulator of peroxisomal lipid metabolism.J. Biol. Chem. 2002; 277: 1128-1138Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar), Acot9 (matrix) (8Tillander V. Arvidsson Nordström E. Reilly J. Strozyk M. Van Veldhoven P.P. Hunt M.C. Alexson S.E. Acyl-CoA thioesterase 9 (ACOT9) in mouse may provide a novel link between fatty acid and amino acid metabolism in mitochondria.Cell. Mol. Life Sci. 2014; 71: 933-948Crossref PubMed Scopus (27) Google Scholar), Acot15/Them5 (matrix) (9Zhuravleva E. Gut H. Hynx D. Marcellin D. Bleck C.K. Genoud C. 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Alexson S.E. acyl-CoA thioesterases a highly novel in lipid metabolism.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M.C. G. C.M. M. C. Alexson S.E. The acid Biol. Chem. Full Text Full Text PDF PubMed Scopus (137) Google Scholar, V. C. role for in mitochondrial to fasting but not in fatty acid oxidation or fatty acid anion Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). major substrates are and Alexson S.E. and acyl-CoA thioesterases in rat liver mitochondria. and by Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), which Acot2 as a potential regulator of long-chain fatty acyl-CoA into FAO. a role for Acot2 has been defined in A. R. P. C. acid in the of in mitochondria of PubMed Scopus Google Scholar, P. R. C. the of mitochondrial acyl-CoA thioesterase I and acyl-CoA J. PubMed Scopus Google Scholar), its role in highly tissues is unknown. we the biological role of Acot2 in we Acot2 in the liver of of adenoviral Acot2 overexpression in mouse liver Ad-Acot2 higher FA utilization during the of the but to carbohydrate oxidation In Ad-Acot2 liver mitochondria, phosphorylating O2 consumption was elevated with lipid substrate, but not nonlipid substrate. the was in Ad-Acot2 liver mitochondria, was our findings that Acot2 FAO. the of Acot2 on mitochondrial substrate oxidation is to FAO and may be of in were from were by the and were on from our were on a to and ad a were overnight to mouse Acot2 by the (Ad-Acot2), or the were and the was in were the were for and not to the were and and activity were in the were and were to to the to were from or mice. were with then was the a to and then to and acid were to was in from a by of the to inhibit were to and then for in the liver, were from by and then in mitochondria were as C. and mechanisms of mitochondrial during long-chain fatty acid Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). were by were on or were in liver and then by was in in a and a were The was again and then for The was in then The was in a minimal of for a of as by were from mice, by in of the liver and The liver was and with an amino acid 9 by the with the and were with in The liver was then with type I in the was by the liver in were and were and overnight in and was the mitochondria were to D. minimal of PubMed Scopus Google Scholar). of the of mitochondria in mitochondrial The was to of mitochondria to the was and again are in the was to were then within in with was during the by and then to The was from the to mitochondrial was in mitochondria and in the of C. and mechanisms of mitochondrial during long-chain fatty acid Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). were to in mitochondrial and to were in a of in were to and was for and then substrate was and was for were by the by activity was a of was by of were to the is the substrate the and the was in of and on for and then was by the mitochondria, an of mitochondria was in of the were an or and with were in Acot2 was of or a from carnitine I II or were in were the were by The liver was and within were the and were by a with an a and a were from mitochondria by a and and Scopus Google Scholar). for of of lipid were to and Scopus Google Scholar). were with a with an with K. the of lipid and of of an for Commun. 2008; PubMed Scopus Google Scholar). and of lipid were a and K. H. lipid and by Chem. PubMed Scopus Google Scholar, K. of lipid by a in PubMed Scopus Google Scholar). and were as S.M. P. C.M. the of the major of the mitochondrial Biol. 2008; PubMed Scopus Google Scholar, S.M. C.M. and of a of Biol. PubMed Scopus Google Scholar). In from of mitochondria were with were and were with were was G. A. then of and of by of PubMed Scopus Google Scholar). The were from and overnight mice, for and and as in G. G. and in from and 2012; PubMed Scopus Google Scholar). were a were mitochondria were was from liver was with for was a was and for were with in was an were and are in the were from are as the and were by or by for by was taken as the role of Acot2 in the liver, we Acot2 adenoviral of mouse Acot2 by of liver of the to mitochondria In and mice, we Acot2 in muscle and and increase in Ad-Acot2 is to Acot2 in the liver, we compared levels of Acot2 to levels from mice. a increase in Acot2 levels were higher the levels whether Acot2 was we thioesterase activity in liver mitochondria. (7Hunt M.C. Solaas K. Kase B.F. Alexson S.E. Characterization of an acyl-coA thioesterase that functions as a major regulator of peroxisomal lipid metabolism.J. Biol. Chem. 2002; 277: 1128-1138Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar), Acot2 overexpression in elevated thioesterase activity and to a and were as the substrate, but not with Using the of Acot2 was for or within the of for the rat Alexson S.E. and acyl-CoA thioesterases in rat liver mitochondria. and by Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The of thioesterase activity in liver mitochondria was higher was between Ad-Acot2 and mitochondria, with a in mitochondria activity in liver mitochondria could from the activity of with the outer mitochondrial J. thioesterase a thioesterase with for long-chain fatty J. PubMed Scopus Google and to the matrix (9Zhuravleva E. Gut H. Hynx D. Marcellin D. Bleck C.K. Genoud C. Cron P. et coenzyme A thioesterase is in and fatty liver Biol. 2012; PubMed Scopus Google the for is to that for (9Zhuravleva E. Gut H. Hynx D. Marcellin D. Bleck C.K. Genoud C. Cron P. et coenzyme A thioesterase is in and fatty liver Biol. 2012; PubMed Scopus Google Scholar). activity in Ad-Acot2 mitochondria with and thioesterase activity was with in with in rat Acot2 Alexson S.E. and acyl-CoA thioesterases in rat liver mitochondria. and by Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). is to would not for J. thioesterase a thioesterase with for long-chain fatty J. PubMed Scopus Google Scholar). the inhibition substrate as was Alexson S.E. and acyl-CoA thioesterases in rat liver mitochondria. and by Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the biological role of Acot2 was in mice. was similar in and Ad-Acot2 on of compared with to was in Ad-Acot2 mice, as by the of and activity were higher in Ad-Acot2 was similar between and Ad-Acot2 mice, whether during the or of the the the which on the substrate for for carbohydrate was in Ad-Acot2 during the of the and then to a similar to that in during the The in was not in Ad-Acot2 mice. acid and in serum and in the liver were elevated in Ad-Acot2 mice. were in liver from mice. and as as and long-chain were higher in Ad-Acot2 liver we in the of mitochondrial the of long-chain fatty into whether in mitochondria or liver or in levels of the hepatic lipid overnight and Ad-Acot2 of their and the with similar a similar of in in the the and of the were similar in and Acot2 in serum and in acid were similar between and Ad-Acot2 serum was in Ad-Acot2 the fasting lipid accumulation was similar between and Ad-Acot2 during the of the then was higher in Ad-Acot2 liver 9 of by the liver was elevated in liver but to levels in Ad-Acot2 The of liver the were by lipid in mice, lipid were on from Ad-Acot2 mice. of hepatic steatosis with fasting has been in of mice, mice, with levels an overnight similar to that we in liver G. fatty acid oxidation in muscle hepatic steatosis in Biol. 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Full Text Full Text PDF PubMed Scopus Google Scholar). from the liver would not the in liver in Ad-Acot2 hepatic to be higher in which is with the higher serum in evidence for lipid accumulation in Ad-Acot2 whether lipid was of in the levels in were similar to levels the The levels of mitochondrial were similar between and whether in liver or mitochondria from the levels in liver that mitochondrial was not in Ad-Acot2 This was by of liver the of mitochondria, the was in Ad-Acot2 liver mitochondria in Ad-Acot2 liver, as by a with in mitochondria the of Ad-Acot2 not The between and Ad-Acot2 mitochondria are with elevated FAO in Ad-Acot2 mitochondria from mice, as The Acot2 could increase the of free in the mitochondrial and free can to in the of This may during are the substrate for oxidation a of we by in mice. the fasting was was similar in and Ad-Acot2 the the were to be higher in Ad-Acot2 mice. whether higher in Ad-Acot2 could for the of liver was in mouse for the of the in This was by the the for mouse that was on the were to mouse to be higher in Ad-Acot2 with of the in the in between the and Ad-Acot2 was which is similar to the in the of hepatic the of the that liver were similar in and Ad-Acot2 and were the of the be that a would be to be by the role for in (9Zhuravleva E. Gut H. Hynx D. Marcellin D. Bleck C.K. Genoud C. Cron P. et coenzyme A thioesterase is in and fatty liver Biol. 2012; PubMed Scopus Google Scholar), and that an role in mitochondrial of in mitochondrial dysfunction and J. PubMed Scopus Google Scholar), we whether in the and of and the in and Ad-Acot2 This to and are not the major substrates of Acot2 overexpression the mitochondrial thioesterase activity for substrates and and to a are major of of and by of mitochondria from an of the to increases in as by a of fatty In were in which was of mitochondria from and the of is the of In was between and Ad-Acot2 mitochondria in the of that the higher FA utilization during the daytime in ad libitum-fed Ad-Acot2 is to in mitochondrial or of in Ad-Acot2 may be to possibly by further into the role of Acot2 in FAO, we to in mitochondria and Acot2 long-chain fatty acyl-CoA into and free and was to mitochondrial β-oxidation by mitigating a mitochondrial FA is J. role of may be of fatty from mitochondria fatty acid oxidation an Biol. PubMed Scopus Google Scholar). Acot2 could FA utilization the released FA in the mitochondrial membrane, a into the matrix for P. fatty as of in rat liver Biophys. PubMed Scopus Google a was in liver mitochondria and which was to whether Acot2 overexpression on substrate oxidation. and Ad-Acot2 liver mitochondria similar and control was between and Ad-Acot2 mitochondria in the and with as the substrate with and in the of was similar between and Ad-Acot2 mitochondria as was activity and of FA substrate were to whether Acot2 could an role substrate is in Ad-Acot2 liver was elevated with and to a with was a in with and The of the could be by carnitine of was a for higher phosphorylating in Ad-Acot2 mitochondria. the between and Ad-Acot2 was and was the Altogether, the phosphorylating nonlipid or lipid that Acot2 FAO, and FA for the of a FA was as the substrate, the CoA was from the a of FA would not be This from the and which carnitine to of the activated FA into mitochondria, and a of CoA of mitochondria from or the and were of a FA was were between and Ad-Acot2 mitochondria in phosphorylating with or was a for phosphorylating with further for a FA by CoA to the as in skeletal muscle mitochondria V. C. role for in mitochondrial to fasting but not in fatty acid oxidation or fatty acid anion Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). the were highly between and were the higher phosphorylating in Ad-Acot2 mitochondria with or but not with that of FA on the outer mitochondrial is for the higher Acot2 is mitochondrial of were in from and Ad-Acot2 and in the an of of in glucose were similar between and Ad-Acot2 of or to the and with similar in and Ad-Acot2 The increase in was by which The in the were a switch to FA as the substrate would be to In Ad-Acot2 by with and by with In was and was by with which is in Ad-Acot2 findings a utilization of FA for by Acot2 mitochondria. which the was to whether Acot2 overexpression a was higher in Ad-Acot2 mitochondria with or increase was in to the higher such that the of to was similar in and Ad-Acot2 mitochondria in the of was in Ad-Acot2 liver mitochondria for suggesting that could in Ad-Acot2 liver mitochondria. were with in the was in Ad-Acot2 mitochondria In mitochondria with was a for a higher with in Ad-Acot2 mitochondria, and the was In expressed as a of to was higher in Ad-Acot2 for and The was higher in Ad-Acot2 as the findings in mitochondria and indicate that Acot2 overexpression a by virtue of their substrate are poised to modulate mitochondrial FAO. we for the the biological role of Acot2 in a that The biological role of Acot2 is of interest in the context of a understanding of mitochondrial FAO is and in the context of the between mitochondrial FAO and cellular metabolic functions such as insulin and lipid Using hepatic Acot2 overexpression we the and in mitochondria that Acot2 mitochondrial FAO, possibly an circuit that would be by the of FA by not support a of Acot2 on mitochondrial in to (9Zhuravleva E. Gut H. Hynx D. Marcellin D. Bleck C.K. Genoud C. Cron P. et coenzyme A thioesterase is in and fatty liver Biol. 2012; PubMed Scopus Google Scholar). in mitochondria and show that Acot2 can contribute to in mitochondria, and from the liver of Acot2 may be to to The in and from indicate that Acot2 to mitochondrial FAO. The during the in Ad-Acot2 a in substrate utilization of FA substrate, but during the daytime is utilization of FA substrate in The elevated during the in Ad-Acot2 that the was in to hepatic FAO. The liver that mitochondrial of FA was the higher levels of long-chain may reversal of with of carnitine esters from or long-chain not H. on the substrate and for Biophys. PubMed Scopus Google Scholar, R.C. and of rat liver carnitine II J. PubMed Scopus Google Scholar). be that skeletal muscle Acot2 was not elevated in Ad-Acot2 mice, suggesting that FA and utilization in skeletal muscle was similar to that for skeletal muscle to be a driver of the higher FA utilization in mice. The mitochondrial findings provide further for elevated FAO in Ad-Acot2 In mice, fasting liver mitochondria to as G. mitochondria are from and Biol. PubMed Scopus Google Scholar). This was in Ad-Acot2 mitochondria from Ad-Acot2 were FA has been in to mitochondria S.M. to mitochondrial dysfunction and insulin resistance in skeletal Biol. 2012; PubMed Scopus Google Scholar). that a of FA within and in to the mitochondria in Ad-Acot2 liver which the of mitochondria that would have with in mitochondria support an of Acot2 to enhance FAO. This is by the higher phosphorylating with or substrates and of from nonlipid substrates were the phosphorylating was in Ad-Acot2 mitochondria substrate with the of The of Ad-Acot2 with higher FA may substrate inhibition of Acot2 substrate or utilization of the FA by The is by the of the in Ad-Acot2 mitochondria. in from and Ad-Acot2 that Acot2 on or on were with nonlipid substrate and This further that Acot2 overexpression not mitochondrial substrate which with the role of (9Zhuravleva E. Gut H. Hynx D. Marcellin D. Bleck C.K. Genoud C. Cron P. et coenzyme A thioesterase is in and fatty liver Biol. 2012; PubMed Scopus Google Scholar). This that Acot2 overexpression not to an on the were with the of the in was similar in and the between and Ad-Acot2 is to have the of a in in and the of a in in Ad-Acot2 could be as a of to from the lipid substrate. is that the better the Ad-Acot2 from the was in the In an to a in between and Ad-Acot2 of were but were a on in and were not of in which not to in the to between and Ad-Acot2 In the context of the findings in and in mitochondria, we that the of a between and Ad-Acot2 in the to that Acot2 is highly and that its is to cellular that were not in In mitochondria, could be by the of control were to in mitochondrial and in mitochondrial as for the in in Ad-Acot2 mice. The that Acot2 could metabolism was to in of the of with metabolism (9Zhuravleva E. Gut H. Hynx D. Marcellin D. Bleck C.K. Genoud C. Cron P. et coenzyme A thioesterase is in and fatty liver Biol. 2012; PubMed Scopus Google Scholar). The in Ad-Acot2 mitochondria that Acot2 can provide substrate for was the in FAO in Ad-Acot2 are to be to in the the of and further support for a role for Acots in is an during the that for and may be during are to between a role for Acot2 in metabolism or an role to provide that are then into by The is by higher levels of and in Ad-Acot2 mitochondria is that the elevated levels of are to of the would be was not to be in Ad-Acot2 mitochondria. Ad-Acot2 mitochondria not show of the in mitochondria from D. J. V. C. J. A. et and skeletal muscle in a mouse model of Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). A is that a of FA in Ad-Acot2 mitochondria is that are to the role of and of in Using mitochondria, we to whether the FA released from Acot2 was effluxed from mitochondria, then on the outer mitochondrial and taken back up by mitochondria to be J. role of may be of fatty from mitochondria fatty acid oxidation an Biol. PubMed Scopus Google Scholar). The of would be the for the would Acot2 to FAO by inhibitory by a build-up of long-chain fatty acyl-CoA esters in the matrix (4van Eunen K. Simons S.M. Gerding A. Bleeker A. den Besten G. Touw C.M. Houten S.M. Groen B.K. Krab K. Reijngoud D.J. et al.Biochemical competition makes fatty-acid beta-oxidation vulnerable to substrate overload.PLOS Comput. Biol. 2013; 9: e1003186Crossref PubMed Scopus (41) Google Scholar, 5Shug A. Lerner E. Elson C. Shrago E. The inhibition of adenine nucleotide translocase activity by oleoyl CoA and its reversal in rat liver mitochondria.Biochem. Biophys. Res. Commun. 1971; 43: 557-563Crossref PubMed Scopus (137) Google Scholar, 6Woldegiorgis G. Yousufzai S.Y. Shrago E. Studies on the interaction of palmitoyl coenzyme A with the adenine nucleotide translocase.J. Biol. Chem. 1982; 257: 14783-14787Abstract Full Text PDF PubMed Google Scholar). higher phosphorylating was in Ad-Acot2 mitochondria with or but not with such a the in Ad-Acot2 mitochondria with to have phosphorylating and higher to the for Acot2 to substrate from oxidation In the provide the FA phosphorylating to be in Ad-Acot2 would the by of substrate from the support the for an circuit to the higher phosphorylating that was with and and The FA of the Acot2 could in the membrane, a for and to P. fatty as of in rat liver Biophys. PubMed Scopus Google Scholar). The in mitochondria and that Acot2 is of an for in was not by Acot2 the of the of the the FA of the Acot2 could have to a in in Ad-Acot2 to in Ad-Acot2 liver, may have been the of of the of to in Ad-Acot2 liver, as in liver, may be the of elevated in the liver to an of by liver mitochondria. would be by activity of Acot2 or by the accumulation of in the matrix be from the that is not an of Acot2 overexpression in the to was not higher in Ad-Acot2 the was In our Acot2 overexpression indicate that Acot2 can enhance the hepatic oxidation of FA in mitochondria, and has the potential to contribute to from the of Acot2 is to FAO. The of Acot2 and the support a for Acot2 in is and FA is the substrate for oxidation. we that the of Acot2 to hepatic steatosis in that Acot2 would be an for lipid The for the of to and for and with acyl-CoA thioesterase model of adenoviral Acot2 overexpression in mouse liver carnitine FAO, FA oxidation O2 consumption liver FA of control O2 consumption