Acetate Revisited: A Key Biomolecule at the Nexus of Metabolism, Epigenetics, and Oncogenesis – Part 2: Acetate and ACSS2 in Health and Disease

Abstract

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.

Acetyl-CoA Metabolism and Histone Acetylation in the Regulation of Aging and Lifespan

“…It will be important to determine if CR increases the relative abundance of ACSS2-S2 compared to ACSS-S1 or stimulates the association of ACSS2 with chromatin in the hypothalamus and hippocampus, which could potentially be responsible for some of the neuroprotective and anti-aging changes that result from CR and intermittent fasting [ 84 ]. An extensive two-part review of mammalian acetate metabolism and ACSS2 function has recently been published [ 52 , 85 ].…”

Acetate Promotes a Differential Energy Metabolic Response in Human HCT 116 and COLO 205 Colon Cancer Cells Impacting Cancer Cell Growth and Invasiveness

“…It has been documented that [ 14 C] acetate (1 mM) is rapidly transported into HCT-15 CRC cells through overexpressed and active monocarboxylate transporters (MCT1 and/or MCT2), whereas acetate enters RKO cells by facilitated diffusion via aquaporins ( 68 ). In the cytosol, acetate is actively transformed by a cytosolic acetate thiokinase (AcK), which is also named acetyl-CoA synthetase-2 (ACSS2) ( 69 ), in an ATP-dependent reaction to form acetyl-CoA. This activated acetate may be used for fatty acid synthesis ( 70 ) that is required for the de novo plasma membrane biosynthesis to support cellular growth.…”

The Metabolic Fates of Pyruvate in Normal and Neoplastic Cells

“…Despite its origination from sources other than pyruvate, mitochondrial acetyl-CoA supplies might remain low in the face of high proliferative demand, vascular insufficiency and nutrient scarcity and thus eventually become rate-limiting in tumors. Acetate, originating in the gut microbiome, or from intracellular deacetylation reactions, and converted to acetyl-CoA by the nucelo-cytoplasmic enzyme acetyl-CoA synthetase 2 (ACCS2) is necessary for the attainment of maximal tumor growth, particularly during hypoxia [ 11 , 266 ]. This could relieve the dependency on mitochondrial-derived acetyl- CoA and citrate that are the canonical starting substrates for de novo lipogenesis while conserving TCA cycle substrates for energy production [ 267 , 268 , 269 ].…”

“…In addition to the above sources, acetate is also derived from the diet and the hydrolysis of acetyl-CoA, [ 11 , 12 , 266 , 270 , 271 ]. However, evidence for its direct synthesis by eukaryotic cells has been largely indirect [ 132 , 272 , 273 ].…”

“…With the exception of the brain, organs with particularly high energy demands such as the heart and kidney normally prefer fatty acids as their primary energy source and skeletal muscles are intermittently dependent on beta-type fatty acid oxidation (β-FAO) in a manner that reflects their workload [ 6 , 7 , 8 , 9 ]. Acetate, whether ingested directly, synthesized by the gut microbiome, derived from various deacetylation reactions or generated from pyruvate itself, also provides a variable and controllable source of acetyl-CoA [ 10 , 11 , 12 ]. Under these conditions, or in response to the metabolic rewiring initiated by energy-demanding processes, pyruvate may be redirected for purposes other than supplying acetyl-CoA.…”