Fatty liver is associated with reduced SIRT3 activity and mitochondrial protein hyperacetylation

Agnieszka A. Kendrick, Mahua Choudhury, Shaikh M. Rahman, Carrie E. McCurdy, Marisa Friederich, Johan L.K. Van Hove, Peter A. Watson, Nicholas Birdsey, Jianjun Bao, David Gius, Michael N. Sack, Enxuan Jing, C. Ronald Kahn, Jacob E. Friedman, Karen R. Jonscher

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240 Scopus citations

Abstract

Acetylation has recently emerged as an important mechanism for controlling a broad array of proteinsmediating cellular adaptation to metabolic fuels. Acetylation is governed, in part, by SIRTs (sirtuins), class III NAD +-dependent deacetylases that regulate lipid and glucose metabolism in liver during fasting and aging. However, the role of acetylation or SIRTs in pathogenic hepatic fuel metabolism under nutrient excess is unknown. In the present study, we isolated acetylated proteins from total liver proteome and observed 193 preferentially acetylated proteins in mice fed on an HFD (high-fat diet) compared with controls, including 11 proteins not previously identified in acetylation studies. Exposure to the HFD led to hyperacetylation of proteins involved in gluconeogenesis, mitochondrial oxidative metabolism, methionine metabolism, liver injury and the ER (endoplasmic reticulum) stress response. Livers of mice fed on the HFD had reduced SIRT3 activity, a 3-fold decrease in hepatic NAD+ levels and increased mitochondrial protein oxidation. In contrast, neither SIRT1 nor histone acetyltransferase activities were altered, implicating SIRT3 as a dominant factor contributing to the observed phenotype. In Sirt3-/- mice, exposure to the HFD further increased the acetylation status of liver proteins and reduced the activity of respiratory complexes III and IV. This is the first study to identify acetylation patterns in liver proteins of HFD-fed mice. Our results suggest that SIRT3 is an integral regulator of mitochondrial function and its depletion results in hyperacetylation of critical mitochondrial proteins that protect against hepatic lipotoxicity under conditions of nutrient excess.

Original languageEnglish
Pages (from-to)505-514
Number of pages10
JournalBiochemical Journal
Volume433
Issue number3
DOIs
StatePublished - Feb 1 2011

Keywords

  • Cellular metabolism
  • Mitochondrial metabolism
  • NAD
  • Non-alcoholic fatty liver disease
  • Obesity
  • Proteomics
  • Sirtuin

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    Kendrick, A. A., Choudhury, M., Rahman, S. M., McCurdy, C. E., Friederich, M., Van Hove, J. L. K., Watson, P. A., Birdsey, N., Bao, J., Gius, D., Sack, M. N., Jing, E., Kahn, C. R., Friedman, J. E., & Jonscher, K. R. (2011). Fatty liver is associated with reduced SIRT3 activity and mitochondrial protein hyperacetylation. Biochemical Journal, 433(3), 505-514. https://doi.org/10.1042/BJ20100791