Histone acetyltransferase NAA40 modulates acetyl-CoA levels and lipid synthesis
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...
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| Format: | Article |
| Language: | English |
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BMC
2022-01-01
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| Series: | BMC Biology |
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| Online Access: | https://doi.org/10.1186/s12915-021-01225-8 |
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| author | Evelina Charidemou Maria A. Tsiarli Andria Theophanous Vural Yilmaz Chrysoula Pitsouli Katerina Strati Julian L. Griffin Antonis Kirmizis |
| author_facet | Evelina Charidemou Maria A. Tsiarli Andria Theophanous Vural Yilmaz Chrysoula Pitsouli Katerina Strati Julian L. Griffin Antonis Kirmizis |
| author_sort | Evelina Charidemou |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T13:44:19Z |
| format | Article |
| id | doaj.art-088b4effe7934dd1b92b80dbd3b551cc |
| institution | Directory Open Access Journal |
| issn | 1741-7007 |
| language | English |
| last_indexed | 2024-12-13T13:44:19Z |
| publishDate | 2022-01-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Biology |
| spelling | doaj.art-088b4effe7934dd1b92b80dbd3b551cc2022-12-21T23:43:29ZengBMCBMC Biology1741-70072022-01-0120111810.1186/s12915-021-01225-8Histone acetyltransferase NAA40 modulates acetyl-CoA levels and lipid synthesisEvelina Charidemou0Maria A. Tsiarli1Andria Theophanous2Vural Yilmaz3Chrysoula Pitsouli4Katerina Strati5Julian L. Griffin6Antonis Kirmizis7Department of Biological Sciences, University of CyprusDepartment of Biological Sciences, University of CyprusDepartment of Biological Sciences, University of CyprusDepartment of Biological Sciences, University of CyprusDepartment of Biological Sciences, University of CyprusDepartment of Biological Sciences, University of CyprusDepartment of Biochemistry and Cambridge Systems Biology Centre, University of CambridgeDepartment of Biological Sciences, University of CyprusAbstract 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.https://doi.org/10.1186/s12915-021-01225-8Histone acetyltransferasesNAA40acetyl-CoALipid metabolismEpigeneticsDrosophila melanogaster |
| spellingShingle | Evelina Charidemou Maria A. Tsiarli Andria Theophanous Vural Yilmaz Chrysoula Pitsouli Katerina Strati Julian L. Griffin Antonis Kirmizis Histone acetyltransferase NAA40 modulates acetyl-CoA levels and lipid synthesis BMC Biology Histone acetyltransferases NAA40 acetyl-CoA Lipid metabolism Epigenetics Drosophila melanogaster |
| title | Histone acetyltransferase NAA40 modulates acetyl-CoA levels and lipid synthesis |
| title_full | Histone acetyltransferase NAA40 modulates acetyl-CoA levels and lipid synthesis |
| title_fullStr | Histone acetyltransferase NAA40 modulates acetyl-CoA levels and lipid synthesis |
| title_full_unstemmed | Histone acetyltransferase NAA40 modulates acetyl-CoA levels and lipid synthesis |
| title_short | Histone acetyltransferase NAA40 modulates acetyl-CoA levels and lipid synthesis |
| title_sort | histone acetyltransferase naa40 modulates acetyl coa levels and lipid synthesis |
| topic | Histone acetyltransferases NAA40 acetyl-CoA Lipid metabolism Epigenetics Drosophila melanogaster |
| url | https://doi.org/10.1186/s12915-021-01225-8 |
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