Impact of High Fat Diet on Tissue Acyl-CoA and Histone Acetylation Levels [Molecular Bases of Disease]

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.

from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2jGe1VW
via IFTTT