Acetylation has recently emerged as an important mechanism for controlling a broad array of proteins mediating 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.
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Research Article|
January 14 2011
Fatty liver is associated with reduced SIRT3 activity and mitochondrial protein hyperacetylation
Agnieszka A. Kendrick;
Agnieszka A. Kendrick
1
*Nutrition and Obesity Research Center (NORC), Mass Spectrometry Core Facility, Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO 80045, U.S.A.
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Mahua Choudhury;
Mahua Choudhury
1
†Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, U.S.A.
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Shaikh M. Rahman;
Shaikh M. Rahman
†Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, U.S.A.
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Carrie E. McCurdy;
Carrie E. McCurdy
†Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, U.S.A.
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Marisa Friederich;
Marisa Friederich
†Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, U.S.A.
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Johan L. K. Van Hove;
Johan L. K. Van Hove
†Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, U.S.A.
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Peter A. Watson;
Peter A. Watson
‡Denver VA Medical Center, Denver, CO 80220, U.S.A.
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Nicholas Birdsey;
Nicholas Birdsey
‡Denver VA Medical Center, Denver, CO 80220, U.S.A.
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Jianjun Bao;
Jianjun Bao
§Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, U.S.A.
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David Gius;
David Gius
2
‖Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, U.S.A.
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Michael N. Sack;
Michael N. Sack
§Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, U.S.A.
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Enxuan Jing;
Enxuan Jing
¶Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, U.S.A.
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C. Ronald Kahn;
C. Ronald Kahn
¶Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, U.S.A.
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Jacob E. Friedman;
Jacob E. Friedman
3
*Nutrition and Obesity Research Center (NORC), Mass Spectrometry Core Facility, Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO 80045, U.S.A.
†Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, U.S.A.
3To whom correspondence should be addressed (email jed.friedman@ucdenver.edu).
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Karen R. Jonscher
Karen R. Jonscher
*Nutrition and Obesity Research Center (NORC), Mass Spectrometry Core Facility, Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO 80045, U.S.A.
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Publisher: Portland Press Ltd
Received:
May 27 2010
Revision Received:
September 30 2010
Accepted:
November 02 2010
Accepted Manuscript online:
November 02 2010
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem J (2011) 433 (3): 505–514.
Article history
Received:
May 27 2010
Revision Received:
September 30 2010
Accepted:
November 02 2010
Accepted Manuscript online:
November 02 2010
Citation
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; Fatty liver is associated with reduced SIRT3 activity and mitochondrial protein hyperacetylation. Biochem J 1 February 2011; 433 (3): 505–514. doi: https://doi.org/10.1042/BJ20100791
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