title: Obesity-induced lysine acetylation increases cardiac fatty acid oxidation and impairs insulin signalling.
abstract: OBJECTIVE
  Lysine acetylation is a novel post-translational pathway that regulates the activities of enzymes involved in both fatty acid and glucose metabolism. We examined whether lysine acetylation controls heart glucose and fatty acid oxidation in high-fat diet (HFD) obese and SIRT3 knockout (KO) mice.
  
  
  RESULTS
  C57BL/6 mice were placed on either a HFD (60% fat) or a low-fat diet (LFD; 4% fat) for 16 or 18 weeks. Cardiac fatty acid oxidation rates were significantly increased in HFD vs. LFD mice (845 ± 76 vs. 551 ± 87 nmol/g dry wt min, P < 0.05). Activities of the fatty acid oxidation enzymes, long-chain acyl-CoA dehydrogenase (LCAD), and β-hydroxyacyl-CoA dehydrogenase (β-HAD) were increased in hearts from HFD vs. LFD mice, and were associated with LCAD and β-HAD hyperacetylation. Cardiac protein hyperacetylation in HFD-fed mice was associated with a decrease in SIRT3 expression, while expression of the mitochondrial acetylase, general control of amino acid synthesis 5 (GCN5)-like 1 (GCN5L1), did not change. Interestingly, SIRT3 deletion in mice also led to an increase in cardiac fatty acid oxidation compared with wild-type (WT) mice (422 ± 29 vs. 291 ± 17 nmol/g dry wt min, P < 0.05). Cardiac lysine acetylation was increased in SIRT3 KO mice compared with WT mice, including increased acetylation and activity of LCAD and β-HAD. Although the HFD and SIRT3 deletion decreased glucose oxidation, pyruvate dehydrogenase acetylation was unaltered. However, the HFD did increase Akt acetylation, while decreasing its phosphorylation and activity.
  
  
  CONCLUSIONS
  We conclude that increased cardiac fatty acid oxidation in response to high-fat feeding is controlled, in part, via the down-regulation of SIRT3 and concomitant increased acetylation of mitochondrial β-oxidation enzymes.
authors: Mazankowski Alberta Heart Institute, University of Alberta, 423 Heritage Medical Research Building, Edmonton, AB, Canada T6G 2S2.
authors: Osama Abo
authors: OA
authors: Alrob
authors: Mazankowski Alberta Heart Institute, University of Alberta, 423 Heritage Medical Research Building, Edmonton, AB, Canada T6G 2S2.
authors: Sowndramalingam
authors: S
authors: Sankaralingam
authors: Mazankowski Alberta Heart Institute, University of Alberta, 423 Heritage Medical Research Building, Edmonton, AB, Canada T6G 2S2.
authors: Cary
authors: C
authors: Ma
authors: Mazankowski Alberta Heart Institute, University of Alberta, 423 Heritage Medical Research Building, Edmonton, AB, Canada T6G 2S2.
authors: Cory S
authors: CS
authors: Wagg
authors: Mazankowski Alberta Heart Institute, University of Alberta, 423 Heritage Medical Research Building, Edmonton, AB, Canada T6G 2S2.
authors: Natasha
authors: N
authors: Fillmore
authors: Mazankowski Alberta Heart Institute, University of Alberta, 423 Heritage Medical Research Building, Edmonton, AB, Canada T6G 2S2.
authors: Jagdip S
authors: JS
authors: Jaswal
authors: National Institutes of Health, Bethesda, MD, USA.
authors: Michael N
authors: MN
authors: Sack
authors: Mazankowski Alberta Heart Institute, University of Alberta, 423 Heritage Medical Research Building, Edmonton, AB, Canada T6G 2S2.
authors: Richard
authors: R
authors: Lehner
authors: Department of Surgery, University of Chicago, Chicago, IL, USA.
authors: Mahesh P
authors: MP
authors: Gupta
authors: Mazankowski Alberta Heart Institute, University of Alberta, 423 Heritage Medical Research Building, Edmonton, AB, Canada T6G 2S2.
authors: Evangelos D
authors: ED
authors: Michelakis
authors: Mazankowski Alberta Heart Institute, University of Alberta, 423 Heritage Medical Research Building, Edmonton, AB, Canada T6G 2S2.
authors: Raj S
authors: RS
authors: Padwal
authors: Mazankowski Alberta Heart Institute, University of Alberta, 423 Heritage Medical Research Building, Edmonton, AB, Canada T6G 2S2.
authors: David E
authors: DE
authors: Johnstone
authors: Mazankowski Alberta Heart Institute, University of Alberta, 423 Heritage Medical Research Building, Edmonton, AB, Canada T6G 2S2.
authors: Arya M
authors: AM
authors: Sharma
authors: Mazankowski Alberta Heart Institute, University of Alberta, 423 Heritage Medical Research Building, Edmonton, AB, Canada T6G 2S2 gary.lopaschuk@ualberta.ca.
authors: Gary D
authors: GD
authors: Lopaschuk
mesh_terms: D000107:Acetylation; D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000378:metabolism; D000818:Animals; D005227:Fatty Acids / Q000378:metabolism*; D006321:Heart / Q000502:physiology; D007328:Insulin / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D010084:Oxidation-Reduction; D015398:Signal Transduction / Q000502:physiology; D056566:Sirtuin 3 / Q000235:genetics* / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D007328:Insulin; C525046:Sirt3 protein, mouse; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D056566:Sirtuin 3; D008239:Lysine
keywords: Akt; B-hydroxyacyl CoA dehydrogenase; Glucose oxidation; Long-chain acyl-CoA dehydrogenase; Lysine acetylation; Obesity; Sirtuin 3