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

Cynthia Moffat, Lavesh Bhatia, Teresa Nguyen, Peter Lynch, Miao Wang, Dongning Wang, Olga R. Ilkayeva, Xianlin Han, Matthew D. Hirschey, Steven M. Claypool, Erin L. Seifert

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

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 effl uxed 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 fi ndings indicate that Acot2 can enhance FAO, possibly by mitigating the accumulation of FAO intermediates within the mitochondrial matrix.

Original languageEnglish (US)
Article numberA3
Pages (from-to)2458-2470
Number of pages13
JournalJournal of lipid research
Volume55
Issue number12
DOIs
StatePublished - Jan 1 2015

Keywords

  • Acyl-coenzyme A
  • Cardiolipin
  • Mitochondria
  • Mitochondrial proton leak
  • Mitochondrial thioesterase
  • Mouse
  • β-oxidation

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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