Histone acetyltransferase NAA40 modulates acetyl-CoA levels and lipid synthesis.
View / Open Files
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
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
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
Drosophila melanogaster, Epigenetics, lipid metabolism, fat body, Metabolic Disorders, Acetyl-coa, Histone Acetyltransferases, Naa40
Sponsorship
Wellcome Trust (093,148/Z/10/Z)
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)
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
PMC8781613, 35057804
External DOI: https://doi.org/10.1186/s12915-021-01225-8
This record's URL: https://www.repository.cam.ac.uk/handle/1810/334296
Statistics
Total file downloads (since January 2020). For more information on metrics see the
IRUS guide.
Recommended or similar items
The current recommendation prototype on the Apollo Repository will be turned off on 03 February 2023. Although the pilot has been fruitful for both parties, the service provider IKVA is focusing on horizon scanning products and so the recommender service can no longer be supported. We recognise the importance of recommender services in supporting research discovery and are evaluating offerings from other service providers. If you would like to offer feedback on this decision please contact us on: support@repository.cam.ac.uk