Impact of a High-fat Diet on Tissue Acyl-CoA and Histone Acetylation Levels

Alessandro Carrer,Joshua L.D Parris,Sophie Trefely,Ryan A Henry,David C Montgomery,Annmarie Torres,John M Viola,Yin-Ming Kuo,Ian A Blair,Jordan L Meier,Andrew J Andrews,Nathaniel W Snyder,Kathryn E Wellen

doi:10.1074/jbc.m116.750620

Abstract

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 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 ATP citrate-lyase 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 mice consuming a HFD have reduced levels of acetyl-CoA and/or acetyl-CoA:CoA ratio in these tissues. In WAT and the pancreas, HFD also impacted the levels of histone acetylation; in particular, histone H3 lysine 23 acetylation was lower in HFD-fed mice. Genetic deletion of Acly in cultured adipocytes also suppressed acetyl-CoA and histone acetylation levels. In the liver, no significant effects on histone acetylation were observed with a 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 P300/CBP-associated factor (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 the liver.

Highlights

Cellular metabolism dynamically regulates the epigenome via availability of the metabolite substrates of chromatin-modifying enzymes
It has become clear that cellular metabolism exerts a profound and dynamic influence on histone modifications because of the fact that metabolic intermediates are substrates in many chromatin-modifying reactions [5,6,7,8,9]
A High-fat Diet Suppresses ATP citrate-lyase (ACLY) and ACSS2 Levels in white adipose tissue (WAT) and Liver—To assess whether diet impacts the levels of histone acetylation and acyl-CoA species within tissues, C57Bl/6 mice were fed either regular chow (RC) or an high-fat diet (HFD) (60% kcal from fat)

Summary

Results

A High-fat Diet Suppresses ACLY and ACSS2 Levels in WAT and Liver—To assess whether diet impacts the levels of histone acetylation and acyl-CoA species within tissues, C57Bl/6 mice were fed either regular chow (RC) or an HFD (60% kcal from fat). Mice consuming the HFD showed a trend toward increased body weight and significantly increase blood glucose levels after 5 days already (Fig. 1, A and B), and both body weight and blood glucose levels were significantly elevated after 4 weeks of dietary intervention (Fig. 1, C and D). 4 weeks of HFD was sufficient to potently suppress levels of the de novo lipogenesis (DNL) proteins ACLY, acyl-CoA synthetase short-chain family member 2 (ACSS2), and fatty acid synthetase (FASN) in perigonadal WAT (pgWAT) (Fig. 2, A and B).

C Liver Regular Chow High Fat Diet

40 H4K12ac

Discussion

A Acetyl-CoA H3K9ac H4K8ac H3K23ac H3K14ac H4K5ac H3K18ac H4K16ac H4K12ac

Experimental Procedures