title: Impact of a High-fat Diet on Tissue Acyl-CoA and Histone Acetylation Levels.
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 ofAclyin 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 activityin vitroThis 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.
authors.affiliation: Department of Cancer Biology, Abramson Family Cancer Research Institute.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Carrer
authors.affiliation: Department of Cancer Biology, Abramson Family Cancer Research Institute.
authors.forename: Joshua L D
authors.initials: JLD
authors.lastname: Parris
authors.affiliation: Department of Cancer Biology, Abramson Family Cancer Research Institute; A. J. Drexel Autism Institute, Drexel University, Philadelphia, Pennsylvania 19104.
authors.forename: Sophie
authors.initials: S
authors.lastname: Trefely
authors.affiliation: Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Henry
authors.affiliation: Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702.
authors.forename: David C
authors.initials: DC
authors.lastname: Montgomery
authors.affiliation: Department of Cancer Biology, Abramson Family Cancer Research Institute.
authors.forename: AnnMarie
authors.initials: A
authors.lastname: Torres
authors.affiliation: Department of Cancer Biology, Abramson Family Cancer Research Institute.
authors.forename: John M
authors.initials: JM
authors.lastname: Viola
authors.affiliation: Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111.
authors.forename: Yin-Ming
authors.initials: YM
authors.lastname: Kuo
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Blair
authors.affiliation: Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702.
authors.forename: Jordan L
authors.initials: JL
authors.lastname: Meier
authors.affiliation: Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Andrews
authors.affiliation: A. J. Drexel Autism Institute, Drexel University, Philadelphia, Pennsylvania 19104.
authors.forename: Nathaniel W
authors.initials: NW
authors.lastname: Snyder
authors.affiliation: Department of Cancer Biology, Abramson Family Cancer Research Institute. Electronic address: wellenk@exchange.upenn.edu.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Wellen
mesh_terms: D001275:ATP Citrate (pro-S)-Lyase / Q000235:genetics / Q000378:metabolism; D000107:Acetylation; D000214:Acyl Coenzyme A / Q000032:analysis / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects; D017353:Gene Deletion; D006657:Histones / Q000032:analysis / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000378:metabolism
chemical_list: D000214:Acyl Coenzyme A; D006657:Histones; D001275:ATP Citrate (pro-S)-Lyase
keywords: Acetyl-CoA; adipose tissue; diet; histone acetylation; liver