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J Biol Chem. 2018 Nov 16;293(46):17676-17684. doi: 10.1074/jbc.AC118.005462. Epub 2018 Oct 15.

The protein acetylase GCN5L1 modulates hepatic fatty acid oxidation activity via acetylation of the mitochondrial β-oxidation enzyme HADHA.

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From the Division of Cardiology.
the Vascular Medicine Institute, and.
the Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261 and.
the Division of Intramural Research, NHLBI, National Institutes of Health, Bethesda, Maryland 20892.
the Division of Endocrinology, Department of Medicine, and.
From the Division of Cardiology,


Sirtuin 3 (SIRT3) deacetylates and activates several mitochondrial fatty acid oxidation enzymes in the liver. Here, we investigated whether the protein acetylase GCN5 general control of amino acid synthesis 5-like 1 (GCN5L1), previously shown to oppose SIRT3 activity, is involved in the regulation of hepatic fatty acid oxidation. We show that GCN5L1 abundance is significantly up-regulated in response to an acute high-fat diet (HFD). Transgenic GCN5L1 overexpression in the mouse liver increased protein acetylation levels, and proteomic detection of specific lysine residues identified numerous sites that are co-regulated by GCN5L1 and SIRT3. We analyzed several fatty acid oxidation proteins identified by the proteomic screen and found that hyperacetylation of hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit α (HADHA) correlates with increased GCN5L1 levels. Stable GCN5L1 knockdown in HepG2 cells reduced HADHA acetylation and increased activities of fatty acid oxidation enzymes. Mice with a liver-specific deletion of GCN5L1 were protected from hepatic lipid accumulation following a chronic HFD and did not exhibit hyperacetylation of HADHA compared with WT controls. Finally, we found that GCN5L1-knockout mice lack HADHA that is hyperacetylated at three specific lysine residues (Lys-350, Lys-383, and Lys-406) and that acetylation at these sites is significantly associated with increased HADHA activity. We conclude that GCN5L1-mediated regulation of mitochondrial protein acetylation plays a role in hepatic metabolic homeostasis.


GCN5L1; HADHA; acetylation; fatty acid oxidation; lipid metabolism; liver metabolism; mitochondria; mitochondrial metabolism; post-translational modification (PTM)

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