title: 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 oxi-dative 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.
authors.affiliation: Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Moffat
authors.affiliation: Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: Lavesh
authors.initials: L
authors.lastname: Bhatia
authors.affiliation: Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: Teresa
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: Peter
authors.initials: P
authors.lastname: Lynch
authors.affiliation: Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL 32827.
authors.forename: Miao
authors.initials: M
authors.lastname: Wang
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27710.
authors.forename: Dongning
authors.initials: D
authors.lastname: Wang
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27710.
authors.forename: Olga R
authors.initials: OR
authors.lastname: Ilkayeva
authors.affiliation: Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL 32827.
authors.forename: Xianlin
authors.initials: X
authors.lastname: Han
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27710.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hirschey
authors.affiliation: Department of Physiology, Johns Hopkins School of Medicine, Baltimore, MD 21205.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Claypool
authors.affiliation: Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Seifert
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism*; D000818:Animals; D050260:Carbohydrate Metabolism; D002478:Cells, Cultured; D002940:Circadian Rhythm; D004734:Energy Metabolism; D005230:Fatty Acids, Nonesterified / Q000097:blood / Q000378:metabolism*; D007657:Ketone Bodies / Q000097:blood; D007700:Kinetics; D050356:Lipid Metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D008930:Mitochondria, Liver / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D010170:Palmitoyl-CoA Hydrolase / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013869:Thiolester Hydrolases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000214:Acyl Coenzyme A; D005230:Fatty Acids, Nonesterified; D007657:Ketone Bodies; D024101:Mitochondrial Proteins; D011994:Recombinant Proteins; D013869:Thiolester Hydrolases; D010170:Palmitoyl-CoA Hydrolase; C500557:mitochondrial acyl-CoA thioesterase I, mouse
keywords: acyl-coenzyme A; cardiolipin; mitochondria; mitochondrial proton leak; mitochondrial thioesterase; mouse; β-oxidation
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