title: Genetic inhibition of hepatic acetyl-CoA carboxylase activity increases liver fat and alters global protein acetylation.
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.
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Jenny D Y
authors.initials: JD
authors.lastname: Chow
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Lawrence
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Marin E
authors.initials: ME
authors.lastname: Healy
authors.affiliation: 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.
authors.forename: John E
authors.initials: JE
authors.lastname: Dominy
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Liao
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Breen
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Frances L
authors.initials: FL
authors.lastname: Byrne
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Brandon M
authors.initials: BM
authors.lastname: Kenwood
authors.affiliation: Institute of Pathology, Medical University Graz, Graz, Austria.
authors.forename: Carolin
authors.initials: C
authors.lastname: Lackner
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Saeko
authors.initials: S
authors.lastname: Okutsu
authors.affiliation: Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Valeria R
authors.initials: VR
authors.lastname: Mas
authors.affiliation: Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Caldwell
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Tomsig
authors.affiliation: Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Cooney
authors.affiliation: 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.
authors.forename: Pere B
authors.initials: PB
authors.lastname: Puigserver
authors.affiliation: Department of Pharmacology, School of Medical Sciences, University of New South Wales, Sydney, Australia.
authors.forename: Nigel
authors.initials: N
authors.lastname: Turner
authors.affiliation: Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
authors.forename: David E
authors.initials: DE
authors.lastname: James
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Judit
authors.initials: J
authors.lastname: Villén
authors.affiliation: 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.
authors.forename: Kyle L
authors.initials: KL
authors.lastname: Hoehn
keywords: Acetylation; Lipid metabolism; Liver; Steatosis