Mouse cardiac acyl coenzyme A synthetase 1 deficiency impairs fatty acid oxidation and induces cardiac hypertrophy

Jessica M. Ellis, Shannon M. Mentock, Michael A. DePetrillo, Timothy R. Koves, Shiraj Sen, Steven M. Watkins, Deborah M. Muoio, Gary W. Cline, Heinrich Taegtmeyer, Gerald I. Shulman, Monte S. Willis, Rosalind A. Coleman

Research output: Contribution to journalArticle

110 Scopus citations

Abstract

Long-chain acyl coenzyme A (acyl-CoA) synthetase isoform 1 (ACSL1) catalyzes the synthesis of acyl-CoA from long-chain fatty acids and contributes the majority of cardiac long-chain acyl-CoA synthetase activity. To understand its functional role in the heart, we studied mice lacking ACSL1 globally (Acsl1T-/-) and mice lacking ACSL1 in heart ventricles (Acsl1 H-/-) at different times. Compared to littermate controls, heart ventricular ACSL activity in Acsl1T-/- mice was reduced more than 90%, acyl-CoA content was 65% lower, and long-chain acyl-carnitine content was 80 to 90% lower. The rate of [14C]palmitate oxidation in both heart homogenate and mitochondria was 90% lower than in the controls, and the maximal rates of [14C]pyruvate and [14C]glucose oxidation were each 20% higher. The mitochondrial area was 54% greater than in the controls with twice as much mitochondrial DNA, and the mRNA abundance of Pgc1α and Errα increased by 100% and 41%, respectively. Compared to the controls, Acsl1T-/- and Acsl1H-/- hearts were hypertrophied, and the phosphorylation of S6 kinase, a target of mammalian target of rapamycin (mTOR) kinase, increased 5-fold. Our data suggest that ACSL1 is required to synthesize the acyl-CoAs that are oxidized by the heart, and that without ACSL1, diminished fatty acid (FA) oxidation and compensatory catabolism of glucose and amino acids lead to mTOR activation and cardiac hypertrophy without lipid accumulation or immediate cardiac dysfunction.

Original languageEnglish (US)
Pages (from-to)1252-1262
Number of pages11
JournalMolecular and cellular biology
Volume31
Issue number6
DOIs
StatePublished - Mar 2011

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Ellis, J. M., Mentock, S. M., DePetrillo, M. A., Koves, T. R., Sen, S., Watkins, S. M., Muoio, D. M., Cline, G. W., Taegtmeyer, H., Shulman, G. I., Willis, M. S., & Coleman, R. A. (2011). Mouse cardiac acyl coenzyme A synthetase 1 deficiency impairs fatty acid oxidation and induces cardiac hypertrophy. Molecular and cellular biology, 31(6), 1252-1262. https://doi.org/10.1128/MCB.01085-10