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Carrer A , Parris JL , Trefely S , Henry RA , Montgomery DC , Torres A , Viola JM , Kuo YM , Blair IA , Meier JL , Andrews AJ , Snyder NW , Wellen KE
Impact of High Fat Diet on Tissue Acyl-CoA and Histone Acetylation Levels
J Biol Chem. 2017 Feb 24;292(8) :3312-3322
PMID: 28077572    PMCID: PMC5336165    URL: https://www.ncbi.nlm.nih.gov/pubmed/28077572
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Cellular metabolism dynamically regulates the epigenome via availability of the metabolite substrates of chromatin-modifying enzymes. The impact of diet on the metabolism-epigenome axis is poorly understood, but could alter gene expression and influence metabolic health. ATP-citrate lyase (ACLY) produces acetyl-CoA in the nucleus and cytosol and regulates histone acetylation levels in many cell types. Consumption of a high fat diet (HFD) results in suppression of ACLY levels in tissues such as adipose and liver, but the impact of diet on acetyl-CoA and histone acetylation in these tissues remains unknown. Here we examined the effects of HFD on levels of acyl-CoAs and histone acetylation in mouse white adipose tissue (WAT), liver, and pancreas. We report that in mice, consuming a HFD reduced levels of acetyl-CoA and/or the acetyl-CoA: CoA ratio in these tissues. In WAT and pancreas, HFD also impacted levels of histone acetylation; in particular, histone H3 lysine 23 acetylation (H3K23ac) was lower in HFD-fed mice. Genetic deletion of Acly in cultured adipocytes also suppressed acetyl-CoA and histone acetylation levels. In liver, no significant effects on histone acetylation were observed with HFD, despite lower acetyl-CoA levels. Intriguingly, acetylation of several histone lysines correlated with the acetyl-CoA: (iso)butyryl-CoA ratio in liver. Butyryl-CoA and isobutyryl-CoA interacted with the acetyltransferase PCAF in liver lysates and inhibited its activity in vitro. This study thus provides evidence that diet can impact tissue acyl-CoA and histone acetylation levels, and that acetyl-CoA abundance correlates with acetylation of specific histone lysines in WAT but not in liver.
1083-351x Carrer, Alessandro ORCID: http://orcid.org/0000-0002-9300-6879 Parris, Joshua L D Trefely, Sophie ORCID: http://orcid.org/0000-0003-3816-6869 Henry, Ryan A Montgomery, David C Torres, AnnMarie ORCID: http://orcid.org/0000-0001-6104-0477 Viola, John M Kuo, Yin-Ming Blair, Ian A Meier, Jordan L Andrews, Andrew J Snyder, Nathaniel W Wellen, Kathryn E ORCID: http://orcid.org/0000-0002-2281-0042 Journal Article United States J Biol Chem. 2017 Jan 11. pii: jbc.M116.750620. doi: 10.1074/jbc.M116.750620.