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

doi:10.1016/j.molmet.2014.02.004

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

Mol Metab. 2014 Mar 12;3(4):419-31. doi: 10.1016/j.molmet.2014.02.004. eCollection 2014 Jul.

Authors

Jenny D Y Chow¹, Robert T Lawrence², Marin E Healy¹, John E Dominy³, Jason A Liao¹, David S Breen¹, Frances L Byrne¹, Brandon M Kenwood¹, Carolin Lackner⁴, Saeko Okutsu¹, Valeria R Mas⁵, Stephen H Caldwell⁵, Jose L Tomsig¹, Gregory J Cooney⁶, Pere B Puigserver³, Nigel Turner⁷, David E James⁶, Judit Villén², Kyle L Hoehn⁸

Affiliations

¹ Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
² Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
³ Department of Cancer Biology, Dana-Faber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA ; Department of Cell Biology, Dana-Faber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
⁴ Institute of Pathology, Medical University Graz, Graz, Austria.
⁵ Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
⁶ Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
⁷ Department of Pharmacology, School of Medical Sciences, University of New South Wales, Sydney, Australia.
⁸ Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA ; Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA ; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia.

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.

Keywords: Acetylation; Lipid metabolism; Liver; Steatosis.

Abstract

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