Obesity-induced lysine acetylation increases cardiac fatty acid oxidation and impairs insulin signalling

Osama Alrob

Sowndramalingam Sankaralingam

Cary Ma

Cory Wagg

Mahesh Gupta+5 authors

Aims

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.

Methods and 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.

Conclusion

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.

Supplementary Material

Supplementary Data:

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^{Mazankowski Alberta Heart Institute, University of Alberta, 423 Heritage Medical Research Building, Edmonton, AB, Canada, T6G 2S2}

^{National Institutes of Health, Bethesda, MD, USA}

^{Department of Surgery, University of Chicago, Chicago, IL, USA}

^{Corresponding author. Tel: +1 780 492 2170; fax: +1 780 492 9753, Email:}ac.atreblau@kuhcsapol.yrag

Received 2014 Feb 17; Revised 2014 Jun 2; Accepted 2014 Jun 5.

Abstract

Aims

Methods and results

Conclusion

Keywords: Lysine acetylation, Long-chain acyl-CoA dehydrogenase, B-hydroxyacyl CoA dehydrogenase, Sirtuin 3, Glucose oxidation, Akt, Obesity

Abstract

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