Format

Send to

Choose Destination
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.

Author information

1
From the Division of Cardiology.
2
the Vascular Medicine Institute, and.
3
the Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261 and.
4
the Division of Intramural Research, NHLBI, National Institutes of Health, Bethesda, Maryland 20892.
5
the Division of Endocrinology, Department of Medicine, and.
6
From the Division of Cardiology, scotti2@upmc.edu.

Abstract

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.

KEYWORDS:

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

PMID:
30323061
PMCID:
PMC6240879
DOI:
10.1074/jbc.AC118.005462
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center