Histone acetyltransferase NAA40 modulates acetyl-CoA levels and lipid synthesis.
Histone acetyltransferase NAA40 modulates acetyl-CoA levels and lipid synthesis.
复制标题
组蛋白乙酰转移酶NAA40调节乙酰辅酶A水平和脂质合成。
DOI：
10.1186/s12915-021-01225-8
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发表时间：
2022-01-20
期刊：
影响因子：
5.4
通讯作者：
Kirmizis A
中科院分区：
文献类型：
--
作者：
Charidemou E;Tsiarli MA;Theophanous A;Yilmaz V;Pitsouli C;Strati K;Griffin JL;Kirmizis A
表观遗传调控依赖于酶的活性，这些酶使用哨兵代谢物作为辅助因子来修饰DNA或组蛋白。因此，细胞代谢物水平的波动已被报道影响染色质修饰。然而，表观遗传修饰剂是否也影响这些代谢物的水平，从而影响下游代谢途径仍然在很大程度上未知。在这里，我们通过研究N-α-乙酰基转移酶40（NAA 40）的功能来测试这一概念，NAA 40是负责组蛋白H2 A和H4的N-末端乙酰化的酶，它以前与代谢相关的疾病有关，如年龄依赖性肝脂肪变性和热量限制介导的长寿。使用代谢组学和脂质组学方法，我们发现小鼠肝细胞中NAA 40的消耗导致细胞内乙酰辅酶A水平的显著增加，这与通过从头脂肪生成基因的上调以及甘油二酯和甘油三酯水平的增加所证明的脂质合成增强有关。一致地，这些脂质种类的增加与细胞质脂滴的积聚和葡萄糖摄取减少所指示的胰岛素信号传导受损一致。然而，NAA 40对脂滴形成的作用不依赖于胰岛素。此外，脂质合成的诱导在果蝇幼虫脂肪体中体内复制。最后，支持我们的研究结果，我们发现NAA 40表达与肥胖患者的胰岛素敏感性有很强的关联。总的来说，我们的研究结果表明，NAA 40影响细胞乙酰辅酶A的水平，从而影响脂质合成和胰岛素信号传导。这项研究揭示了一个新的途径，通过组蛋白修饰酶影响细胞代谢与代谢紊乱的潜在影响。在线版本包含补充材料，可通过10.1186/s12915-021-01225-8获得。
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. 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. 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. The online version contains supplementary material available at 10.1186/s12915-021-01225-8.
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