Genetic inhibition of hepatic acetyl-CoA carboxylase activity increases liver fat and alters global protein acetylation

Jenny D Y Chow, Robert T. Lawrence, Marin E. Healy, John E. Dominy, Jason A. Liao, David S. Breen, Frances L. Byrne, Brandon M. Kenwood, Carolin Lackner, Saeko Okutsu, Valeria R. Mas, Stephen H. Caldwell, Jose L. Tomsig, Gregory J. Cooney, Pere B. Puigserver, Nigel Turner, David E. James, Judit Villén, Kyle L. Hoehn

Research output: Contribution to journalArticle

Abstract

Lipid deposition in the liver is associated with metabolic disorders including fatty liver disease, type II diabetes, and hepatocellular cancer. The enzymes acetyl-CoA carboxylase 1 (ACC1) and ACC2 are powerful regulators of hepatic fat storage; therefore, their inhibition is expected to prevent the development of fatty liver. In this study we generated liver-specific ACC1 and ACC2 double knockout (LDKO) mice to determine how the loss of ACC activity affects liver fat metabolism and whole-body physiology. Characterization of LDKO mice revealed unexpected phenotypes of increased hepatic triglyceride and decreased fat oxidation. We also observed that chronic ACC inhibition led to hyper-acetylation of proteins in the extra-mitochondrial space. In sum, these data reveal the existence of a compensatory pathway that protects hepatic fat stores when ACC enzymes are inhibited. Furthermore, we identified an important role for ACC enzymes in the regulation of protein acetylation in the extra-mitochondrial space.

Original languageEnglish (US)
Pages (from-to)419-431
Number of pages13
JournalMolecular Metabolism
Volume3
Issue number4
DOIs
StatePublished - 2014
Externally publishedYes

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Keywords

  • Acetylation
  • Lipid metabolism
  • Liver
  • Steatosis

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Chow, J. D. Y., Lawrence, R. T., Healy, M. E., Dominy, J. E., Liao, J. A., Breen, D. S., Byrne, F. L., Kenwood, B. M., Lackner, C., Okutsu, S., Mas, V. R., Caldwell, S. H., Tomsig, J. L., Cooney, G. J., Puigserver, P. B., Turner, N., James, D. E., Villén, J., & Hoehn, K. L. (2014). Genetic inhibition of hepatic acetyl-CoA carboxylase activity increases liver fat and alters global protein acetylation. Molecular Metabolism, 3(4), 419-431. https://doi.org/10.1016/j.molmet.2014.02.004