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Fatty liver is associated with reduced SIRT3 activity and mitochondrial protein hyperacetylation
Open accessAbstract
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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“Patients with NAFLD present with decreased ETC complex activity153,154 and a fatty liver-associated decrease in SIRT3 activity, which leads to hyperacetylation of mitochondrial proteins and mitochondrial dysfunction155.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [155]
In the citing paper
“SIRT3, a member located in the mitochondria, seems to a very important role in the regulation of mitochondrial activity especially in fat metabolism”
From Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity (2017) · cites this paper as Kendrick et al., 2011
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Metadata
- Authors
- 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.
- Affiliations
- University of Colorado Anschutz (US)
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, U.S.A.
- Denver VA Medical Center (US)
- National Institutes of Health (US)
- Joslin Diabetes Center (US)
- ORCID
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2011-01-14
- Volume
- 433
- Issue
- 3
- Pages
- 505-514
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC3398511
- OpenAlex
- W2087439645
- Cited by
- 382
- References
- 56
- Citations by year
- 2026: 13 · 2025: 10 · 2024: 14 · 2023: 21 · 2022: 31 · 2021: 16 · 2020: 31 · 2019: 27 · 2018: 38 · 2017: 25 · 2016: 24 · 2015: 25 · 2014: 24 · 2013: 42 · 2012: 24
- FWCI
- 10.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biochemical Journal (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (ZIAHL006047, ZIAHL005199)
- National Institute of Diabetes and Digestive and Kidney Diseases (R24DK085610, R01DK059767, DK59767, P30DK048520, P30-DK 48520)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12HD057022)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- hepatic steatosis, SIRT3, protein hyperacetylation, mitochondrial protein acetylation, high-fat diet, hepatic lipotoxicity, mitochondrial oxidative metabolism, NAD+ depletion, endoplasmic reticulum stress, gluconeogenesis, methionine metabolism, liver injury, SIRT3 knockout mice
- MeSH terms
- Acetylation, Animals, Diet, Energy Metabolism, Fatty Liver, Mice, Knockout, Cell Respiration, Mitochondrial Proteins, Proteomics, Lipid Metabolism, Mice, Sirtuin 3
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