Histone acetyltransferase NAA40 modulates acetyl-CoA levels and lipid synthesis.
Authors
Charidemou, Evelina
Tsiarli, Maria A
Theophanous, Andria
Yilmaz, Vural
Pitsouli, Chrysoula
Strati, Katerina
Griffin, Julian L
Publication Date
2022-01-20Journal Title
BMC Biol
ISSN
1741-7007
Publisher
Springer Science and Business Media LLC
Volume
20
Issue
1
Language
en
Type
Article
This Version
VoR
Metadata
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Charidemou, E., Tsiarli, M. A., Theophanous, A., Yilmaz, V., Pitsouli, C., Strati, K., Griffin, J. L., & et al. (2022). Histone acetyltransferase NAA40 modulates acetyl-CoA levels and lipid synthesis.. BMC Biol, 20 (1) https://doi.org/10.1186/s12915-021-01225-8
Abstract
BACKGROUND: Epigenetic regulation relies on the activity of enzymes that use sentinel metabolites as cofactors to modify DNA or histone proteins. Thus, fluctuations in cellular metabolite levels have been reported to affect chromatin modifications. However, whether epigenetic modifiers also affect the levels of these metabolites and thereby impinge on downstream metabolic pathways remains largely unknown. Here, we tested this notion by investigating the function of N-alpha-acetyltransferase 40 (NAA40), the enzyme responsible for N-terminal acetylation of histones H2A and H4, which has been previously implicated with metabolic-associated conditions such as age-dependent hepatic steatosis and calorie-restriction-mediated longevity. RESULTS: Using metabolomic and lipidomic approaches, we found that depletion of NAA40 in murine hepatocytes leads to significant increase in intracellular acetyl-CoA levels, which associates with enhanced lipid synthesis demonstrated by upregulation in de novo lipogenesis genes as well as increased levels of diglycerides and triglycerides. Consistently, the increase in these lipid species coincide with the accumulation of cytoplasmic lipid droplets and impaired insulin signalling indicated by decreased glucose uptake. However, the effect of NAA40 on lipid droplet formation is independent of insulin. In addition, the induction in lipid synthesis is replicated in vivo in the Drosophila melanogaster larval fat body. Finally, supporting our results, we find a strong association of NAA40 expression with insulin sensitivity in obese patients. CONCLUSIONS: Overall, our findings demonstrate that NAA40 affects the levels of cellular acetyl-CoA, thereby impacting lipid synthesis and insulin signalling. This study reveals a novel path through which histone-modifying enzymes influence cellular metabolism with potential implications in metabolic disorders.
Keywords
Research Article, Histone acetyltransferases, NAA40, acetyl-CoA, Lipid metabolism, Epigenetics, Drosophila melanogaster, Fat body, Metabolic disorders
Sponsorship
H2020 Marie Skłodowska-Curie Actions (890750)
European Regional Development Fund and the Republic of Cyprus through the Research & Innovation Foundation (EXCELLENCE/0918/0081, EXCELLENCE/0918/0105 & EXCELLENCE/1216/0215)
Wellcome Trust (093,148/Z/10/Z)
the Medical Research Council (G0801841 & UD99999906)
the European Regional Development Fund and the Republic of Cyprus through the Research & Innovation Foundation (OPPORTUNITY/0916/ERC-StG/003,INFRASTRUCTURES/1216/0034POST-DOC/0916/0111, INTERNATIONAL/OTHER/0118/0018)
Identifiers
s12915-021-01225-8, 1225
External DOI: https://doi.org/10.1186/s12915-021-01225-8
This record's URL: https://www.repository.cam.ac.uk/handle/1810/333220
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
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