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

Research paper by Jenny D Y JD Chow, Robert T RT Lawrence, Marin E ME Healy, John E JE Dominy, Jason A JA Liao, David S DS Breen, Frances L FL Byrne, Brandon M BM Kenwood, Carolin C Lackner, Saeko S Okutsu, Valeria R VR Mas, Stephen H SH Caldwell, Jose L JL Tomsig, Gregory J GJ Cooney, Pere B PB Puigserver, et al.

Indexed on: 20 Jun '14Published on: 20 Jun '14Published in: Molecular Metabolism



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.

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