Moffett John R, Puthillathu Narayanan, Vengilote Ranjini, Jaworski Diane M, Namboodiri Aryan M
Department of Anatomy, Physiology and Genetics, and Neuroscience Program, Uniformed Services University of the Health Sciences, Bethesda, MD, United States.
Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, VT, United States.
Front Physiol. 2020 Nov 12;11:580171. doi: 10.3389/fphys.2020.580171. eCollection 2020.
Acetate, the shortest chain fatty acid, has been implicated in providing health benefits whether it is derived from the diet or is generated from microbial fermentation of fiber in the gut. These health benefits range widely from improved cardiac function to enhanced red blood cell generation and memory formation. Understanding how acetate could influence so many disparate biological functions is now an area of intensive research. Protein acetylation is one of the most common post-translational modifications and increased systemic acetate strongly drives protein acetylation. By virtue of acetylation impacting the activity of virtually every class of protein, acetate driven alterations in signaling and gene transcription have been associated with several common human diseases, including cancer. In part 2 of this review, we will focus on some of the roles that acetate plays in health and human disease. The acetate-activating enzyme acyl-CoA short-chain synthetase family member 2 (ACSS2) will be a major part of that focus due to its role in targeted protein acetylation reactions that can regulate central metabolism and stress responses. ACSS2 is the only known enzyme that can recycle acetate derived from deacetylation reactions in the cytoplasm and nucleus of cells, including both protein and metabolite deacetylation reactions. As such, ACSS2 can recycle acetate derived from histone deacetylase reactions as well as protein deacetylation reactions mediated by sirtuins, among many others. Notably, ACSS2 can activate acetate released from acetylated metabolites including N-acetylaspartate (NAA), the most concentrated acetylated metabolite in the human brain. NAA has been associated with the metabolic reprograming of cancer cells, where ACSS2 also plays a role. Here, we discuss the context-specific roles that acetate can play in health and disease.
乙酸盐作为最短链的脂肪酸，无论来源于饮食还是肠道中纤维的微生物发酵，都被认为对健康有益。这些健康益处广泛，从改善心脏功能到增强红细胞生成和记忆形成。了解乙酸盐如何影响如此众多不同的生物学功能，是目前一个深入研究的领域。蛋白质乙酰化是最常见的翻译后修饰之一，全身乙酸盐水平升高会强烈推动蛋白质乙酰化。由于乙酰化几乎影响每一类蛋白质的活性，乙酸盐驱动的信号传导和基因转录改变与包括癌症在内的几种常见人类疾病有关。在本综述的第2部分中，我们将重点关注乙酸盐在健康和人类疾病中所起的一些作用。乙酸盐激活酶酰基辅酶A短链合成酶家族成员2（ACSS2）将是该重点的主要部分，因为它在靶向蛋白质乙酰化反应中发挥作用，可调节中心代谢和应激反应。ACSS2是唯一已知的能够回收细胞胞质和细胞核中脱乙酰化反应产生的乙酸盐的酶，包括蛋白质和代谢物脱乙酰化反应。因此，ACSS2可以回收来自组蛋白脱乙酰酶反应以及由去乙酰化酶介导的蛋白质脱乙酰化反应等产生的乙酸盐。值得注意的是，ACSS2可以激活从乙酰化代谢物释放的乙酸盐，包括N-乙酰天门冬氨酸（NAA），它是人类大脑中最浓缩的乙酰化代谢物。NAA与癌细胞的代谢重编程有关，ACSS2在其中也发挥作用。在这里，我们讨论乙酸盐在健康和疾病中可能发挥的特定背景作用。
