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;11:580167. doi: 10.3389/fphys.2020.580167. eCollection 2020.
Acetate is a major end product of bacterial fermentation of fiber in the gut. Acetate, whether derived from the diet or from fermentation in the colon, has been implicated in a range of health benefits. Acetate is also generated in and released from various tissues including the intestine and liver, and is generated within all cells by deacetylation reactions. To be utilized, all acetate, regardless of the source, must be converted to acetyl coenzyme A (acetyl-CoA), which is carried out by enzymes known as acyl-CoA short-chain synthetases. Acyl-CoA short-chain synthetase-2 (ACSS2) is present in the cytosol and nuclei of many cell types, whereas ACSS1 is mitochondrial, with greatest expression in heart, skeletal muscle, and brown adipose tissue. In addition to acting to redistribute carbon systemically like a ketone body, acetate is becoming recognized as a cellular regulatory molecule with diverse functions beyond the formation of acetyl-CoA for energy derivation and lipogenesis. Acetate acts, in part, as a metabolic sensor linking nutrient balance and cellular stress responses with gene transcription and the regulation of protein function. ACSS2 is an important task-switching component of this sensory system wherein nutrient deprivation, hypoxia and other stressors shift ACSS2 from a lipogenic role in the cytoplasm to a regulatory role in the cell nucleus. Protein acetylation is a critical post-translational modification involved in regulating cell behavior, and alterations in protein acetylation status have been linked to multiple disease states, including cancer. Improving our fundamental understanding of the "acetylome" and how acetate is generated and utilized at the subcellular level in different cell types will provide much needed insight into normal and neoplastic cellular metabolism and the epigenetic regulation of phenotypic expression under different physiological stressors. This article is Part 1 of 2 - for Part 2 see doi: 10.3389/fphys.2020.580171.
乙酸盐是肠道中纤维细菌发酵的主要终产物。乙酸盐，无论来源于饮食还是结肠发酵，都与一系列健康益处相关。乙酸盐也在包括肠道和肝脏在内的各种组织中产生并释放出来，并且在所有细胞内通过脱乙酰化反应生成。为了被利用，所有乙酸盐，无论来源如何，都必须转化为乙酰辅酶A（acetyl-CoA），这是由称为酰基辅酶A短链合成酶的酶来完成的。酰基辅酶A短链合成酶-2（ACSS2）存在于许多细胞类型的细胞质和细胞核中，而ACSS1存在于线粒体中，在心脏、骨骼肌和棕色脂肪组织中表达最高。除了像酮体一样在全身重新分配碳之外，乙酸盐正被认为是一种细胞调节分子，其功能多样，不仅仅是形成用于能量产生和脂肪生成的乙酰辅酶A。乙酸盐部分地作为一种代谢传感器，将营养平衡和细胞应激反应与基因转录以及蛋白质功能的调节联系起来。ACSS2是这个传感系统的一个重要任务转换组件，其中营养剥夺、缺氧和其他应激源会使ACSS2从细胞质中的脂肪生成作用转变为细胞核中的调节作用。蛋白质乙酰化是一种关键的翻译后修饰，参与调节细胞行为，蛋白质乙酰化状态的改变与多种疾病状态有关，包括癌症。提高我们对“乙酰化组”以及乙酸盐在不同细胞类型的亚细胞水平上如何产生和利用的基本理解，将为正常和肿瘤细胞代谢以及不同生理应激源下表型表达的表观遗传调控提供急需的见解。本文是系列文章的第1部分，第2部分见doi: 10.3389/fphys.2020.580171。
