Fatty liver is associated with reduced SIRT3 activity and mitochondrial protein hyperacetylation.
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.
Nutrition and Obesity Research Center, Department of Anesthesiology, University of Colorado School of Medicine, Aurora, 80045, USA.
Agnieszka A
AA
Kendrick
Mahua
M
Choudhury
Shaikh M
SM
Rahman
Carrie E
CE
McCurdy
Marisa
M
Friederich
Johan L K
JL
Van Hove
Peter A
PA
Watson
Nicholas
N
Birdsey
Jianjun
J
Bao
David
D
Gius
Michael N
MN
Sack
Enxuan
E
Jing
C Ronald
CR
Kahn
Jacob E
JE
Friedman
Karen R
KR
Jonscher
D000107:Acetylation; D000818:Animals; D019069:Cell Respiration; D004032:Diet; D004734:Energy Metabolism; D005234:Fatty Liver / Q000209:etiology* / Q000378:metabolism; D050356:Lipid Metabolism; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000032:analysis / Q000378:metabolism*; D040901:Proteomics; D056566:Sirtuin 3 / Q000378:metabolism*
D024101:Mitochondrial Proteins; D056566:Sirtuin 3