Where is acetate found

It is produced from natural sources like cotton or wood chips. Because acetate as a source of polymer, it is often used to create printing materials like plastic film, medical supplies, optic frames, and industrial tools. Cellulose acetate is clear and shiny on both sides of the sheet. It is used to produce overlays, graphic arts, and prints. It is biodegradable and has been used in the printing industry for decades because of its stable performance process. Matte acetate is one-sided which allows for prints that contains ink, pen, or pencil.

Acetate is also used in the printing industry to produce acetate film which is a transparent, plastic strip used to create negatives, graphics, and laminates. Ethyl acetate EAC is an ester compound commonly used as a solvent in the printing industry that is composed of a C 4 H 8 O 2 formula. Ethyl acetate is also used as a solvent in inks to produce rotogravure and flexographic printing materials.

The fundamental use of ethyl acetate for both rotogravure and flexographic printing processes is to act as a solvent that dissolves the resin, maintains the ink drying rate, and manages adhesiveness. Because of its widely used popularity, businesses often utilize ethyl acetate in products made in the United States, Europe, China, and South-East Asia.

For best results, you should order black and white prints on standard acetate and color prints on paper-backed acetate sheets. C competes with acetyl-CoA for binding to the enzyme and by varying concentrations of C, they were able to demonstrate that p has distinct conformations that alter its substrate specificity. They showed that acetyl-CoA levels shift the substrate specificity of p, and this alters which histone lysine sites get acetylated.

Because ACSS2 can increase the level of acetyl-CoA locally in the nucleus, where protein deacetylation is robust, ACSS2 activity shifts the set of histone sites that become acetylated based on local substrate availability. As such, local acetate in the nucleus will drive shifts in substrate preference for histone acetyltransferases.

This provides additional flexibility in how ACSS2 links nutrient levels to transcription. Further, the set of transcription factors that are acetylated by ACSS2 will no doubt shift based on various physiological stressors.

It is likely that the shifts in both histone and transcription factor acetylation are coordinated to open the correct chromatin sites for the associated transcription factors to gain access to appropriate promoter sites. All of them have been associated with cancer progression. The mitochondrial forms, ACSS1 and ACSS3, most likely play a significant role in energy derivation via oxidation of acetate and propionate, respectively, but may be less involved in regulatory functions in cancer cells than ACSS2.

One possibility that has not been investigated to our knowledge is that ACSS1 facilitates specific acetylation reactions in the mitochondrial matrix. In such a scenario, ACSS1 would bind to specific protein complexes in the matrix and directly provide acetyl-CoA for targeted acetylation reactions, which could alter the TCA cycle and central metabolism.

One study of human hepatocellular carcinomas showed that tumor subtypes could be stratified based on acetate metabolism Bjornson et al.

Interestingly, increased expression of ACSS1 the mitochondrial form involved in acetate oxidation was associated with the tumor subtype with the lowest patient survival rate. As such, the two mitochondrial forms were associated with the lowest and highest survival groups, suggesting distinct roles for these similarly localized isoforms.

This may be due to their different substrate preferences acetate for ACSS1 vs. Chang et al. They also showed that growth of human gastric adenocarcinoma cells in culture could be blocked by a combination of nutrient deprivation and ACSS3 knockdown.

Further, histone acetylation was reduced by ACSS3 knockdown. Both of these studies Chang et al. This could be accomplished if the acetyl-CoA generated by ACSS3 was utilized by citrate synthase, followed by export of citrate to the cytoplasm and then the nucleus. It is likely that in some cancers this route of acetate utilization is important. However, these results are in conflict with enzyme assays that show ACSS3 preferentially utilizes propionate as substrate Yoshimura et al.

These discrepancies will have to be reconciled by future studies that demonstrate whether ACSS3 can indeed utilize acetate at concentrations and conditions found in the mitochondrial matrix, and that ACSS1 is not the preferred route in some cancers. ACSS2 is present in the cytoplasm and nucleus of most cell types. However, it is expressed at much higher levels in cell nuclei in the rat brain Ariyannur et al. The strong nuclear localization of ACSS2 in many cell types has often been overlooked, in part due to the role of ACSS2 in cytoplasmic lipid synthesis.

This type of translocation is associated with hormonal and transcription factor signaling from the cell periphery to the cell nucleus to induce or enhance the transcription of specific genes. Mounting evidence indicates that this applies to ACSS2.

It is clear that ACSS2 is involved in a number of regulatory roles affecting gene transcription, as is the case with other enzymes that can be recruited to transcription factor complexes. However, ACSS2 is unique in that it is the only known enzyme capable of utilizing free acetate in cell nuclei.

This places ACSS2 in a position to provide localized acetyl-CoA in response to any local increase in acetate levels within the nucleus. As such, ACSS2 helps fuel all acetyltransferases that operate in the cell nucleus. Therefore, ACSS2 can influence gene transcription through two critically important types of acetylation reactions; the acetylation of specific of histones and transcription factors Figure 3. It is in these two roles of facilitating histone and transcription factor acetylation that ACSS2 can affect metabolic reprograming and cell cycle progression in cancer cells through epigenetic means.

Figure 3. Simplified schematic of the dual roles of ACSS2 in the modulation of transcription in cell nuclei. ACSS2 is involved in the modulation of selective transcription factors by at least two mechanisms. By acting to selectively acetylate ac certain histones, ACSS2 facilitates opening of nucleosomes shown in purple at specific gene promoter regions Pr.

Further, ACSS2 is also involved in enhancing transcription of those genes via acetylation of transcription factor complexes. ACSS2 acts in the nucleus by additional acetylation mechanisms, for example, many nuclear-localized enzymes are activated or deactivated by ACSS2-facilitated acetylation, including ACSS2 itself, which is inactivated by acetylation. Intriguingly, adult ACSS2 knockout mice appear phenotypically normal, however, they exhibit reduced tumor burdens in models of hepatic cancer Huang et al.

Paradoxically, in other studies decreased expression of ACSS2 promotes metastasis and predicts poor prognosis in hepatocellular carcinoma Sun et al. Reconciling these discrepancies will be critical for understanding the actions associated with ACSS2 in cancer cells. Studies on acetate utilization via ACSS2 in cancer have shown that acetate is released by cancer cells under hypoxic conditions, and that inhibition of ACSS2 reduces acetate production and release Yoshii et al.

The authors proposed that ACSS2 in cancer cells is capable of running the reverse reaction and generating acetate from existing acetyl-CoA.

These investigators also reported that tumor cells take up and metabolize acetate to lipids Yoshii et al. Such studies emphasize the traditional role of ACSS2 in lipid synthesis and suggest that acetate supports biomass accumulation in cancer cells under hypoxic conditions.

Acetate utilization has also been documented in glioblastoma grade IV astrocytoma , the most common adult primary brain tumor. Using human orthotopic tumors in mice and infusions of 13 C-labeled glucose, acetate, and glutamine, Mashimo et al. In orthotopic glioblastoma tumors, the ratio shifted to approximately equal oxidation of both substrates. They also noted that the increase in acetate utilization can be explained in part by the fact that glioblastoma cells are derived from astrocytes, which are known to avidly take up and oxidize acetate Waniewski and Martin, Further, they proposed that ACSS2 was responsible for the increased acetate oxidation by glioblastoma cells, even though acetyl-CoA generated in the cytoplasm and nucleus cannot gain access to the mitochondrial matrix, where acetate oxidation occurs.

Studies with ACSS2 knockout mice confirmed earlier work showing that the enzyme was involved in both lipid synthesis and histone acetylation. Comerford et al. Paradoxically, Hur et al. Similarly, loss of ACSS2 expression was associated with increased aggressiveness and progression of colorectal cancer Bae et al. Clearly, ACSS2 can have contradictory actions in different tumor types, further highlighting the fact that its actions in oncogenesis and tumor progression involve more than lipid synthesis.

In a fascinating series of experiments using Acss2 knockout mice, Huang et al. When fed a high-fat diet, Acss2 knockout mice did not become as obese as wild-type mice and did not develop hepatic steatosis like the wild-type mice. Further, in the fasted knockout mice, serum glucose and ketone bodies were reduced, whereas serum non-esterified fatty acid levels were increased. Indeed, Acss2 knockout had wide-ranging effects on nutrient uptake, metabolism and utilization that were tissue-specific.

Huang et al. In this same context, ACSS2 can reprogram cancer cells to adapt to nutrient deprivation and other stressors, such as hypoxia. Our early immunohistochemical studies into the localization of ACSS2 surprisingly demonstrated that expression in the rat brain was predominantly nuclear, rather than cytoplasmic Ariyannur et al.

In the first detailed examination of ACSS2 expression in the brain, we observed nuclear expression in all major cell types including neurons, oligodendrocytes, and astrocytes. In normal adult rats, ACSS2 expression was modest and was present in a relatively small number of cell nuclei throughout the brain.

It was also present in the cytoplasm, nucleus, and axons of select neurons in the brainstem, cranial nerve ganglia, and spinal cord. In contrast, many more cells strongly expressed ACSS2 in their nuclei during postnatal brain development and in response to experimental brain injury discussed in part 1 of this review. The large increase in the number of cells with nuclear ACSS2 expression during development and in response to injury strongly implicated ACSS2 in nuclear acetylation reactions and transcriptional regulation required for cellular differentiation, stress responses, and repair Ariyannur et al.

More recent studies have shown that in cancer cells, ACSS2 is expressed in cell nuclei, where it operates to recycle acetate derived from HDAC-mediated deacetylation reactions during hypoxia Bulusu et al. Similar results have been obtained in studies of spermatogenic cells, wherein ACSS2 was localized to the nucleus and acted to recycle acetate derived from HDAC reactions Goudarzi and Amiri-Yekta, Hypoxia is often associated with the tumor microenvironment, and tumor tissue responds by activation of the transcription factor hypoxia inducible factor HIF reviewed in Ratcliffe, The HIF transcriptional control system is complicated and regulates a wide array of signaling pathways.

The functional roles of acetate in cancer cell proliferation remain to be determined, yet it is clear that they are dependent on the cell type from which the cancer was derived Pandey et al.

While acetate could promote energy derivation via ACSS1, or lipogenesis for biomass accumulation via ACSS2, it could also act to regulate metabolic pathways by shifting the pattern of histone and transcription factor acetylation. Erythropoietin is synthesized extensively in the kidney and liver of adult mammals and is involved in controlling erythrocyte production. Erythropoietin synthesis is regulated by the stress-responsive transcription factor HIF Similarly, in cancer cells exposed to glucose or oxygen deprivation, there is an increase in intracellular acetate levels and translocation of ACSS2 from the cytoplasm to the nucleus.

These studies emphasized the regulatory role of transcription factor acetylation in the control of erythropoietin gene expression during pathophysiological states marked by tissue hypoxia, and the key role played by ACSS2 in mediating this response. Li et al. These investigators posit that nutrient deprivation in the tumor microenvironment elicits nuclear translocation of ACSS2 to provide an efficient method for reconverting the acetate generated from deacetylation reactions to acetyl-CoA for use in re-acetylating histones in subsequent chromatin remodeling events Li et al.

This will be discussed in more detail below in the context of NAA signaling. In other studies, the expression levels of ACSS2-pS were analyzed by immunohistochemistry in surgical specimens from non-small-cell lung carcinoma patients Yang et al.

Increased expression of ACSS2-pS in tumors as compared with normal surrounding tissue was identified as a reliable prognostic marker for patients with poor survival rates. In another study of esophageal squamous carcinoma cells in culture, the cancer cells were found to be less sensitive to nutrient deprivation than normal cells. Recently, two alternative transcription start sites for the ACSS2 gene have been identified in hepatocellular carcinoma cells that may help explain the dual role of ACSS2 in promoting and inhibiting cancer aggressiveness Wang et al.

The two isoforms of ACSS2 had different subcellular localization and action. Such findings indicate that ACSS2 has a broader functional repertoire than acting as a salvage pathway for reclaiming acetate, and more than a parallel pathway to ACLY for cytoplasmic acetyl-CoA production.

We suggest that ACSS2 is an important modulator of the integrated stress response ISR in many cell types, including acting as a transcriptional modulator in cellular responses to infection and injury. If ACSS2 associates specifically with certain transcription factors and provides the necessary acetyl-CoA in a local on-demand basis, then it may be a key regulatory agent in epigenetic control of many cell functions associated with nutrient or oxygen deprivation.

It is likely that ACSS2 acts to amplify the activity of a wide range of regulatory pathways. However, acetate and ACSS2 are involved in numerous additional regulatory functions other than responding to nutrient and oxygen deprivation. For example, both the substrate and enzyme are involved in regulatory actions in monocyte-derived dendritic cells in response to signals including zymosan and lipopolysaccharide.

Results suggested that when acetyl-CoA formation from pyruvate was low, ACSS2 replenished the cytoplasmic and nuclear supplies, thus supporting cytokine transcription Marquez et al.

This is where we turn our attention now. In early studies, the levels of NAA in several peripheral tissues had been reported to be extremely low Miyake et al.

This conclusion was overturned when increased NAA levels were found in ovarian cancers Kolwijck et al. In , Pessentheiner et al. Also in , we showed that NAA promoted growth and inhibited differentiation of tumor derived glioma stem-like cells in culture Long et al. Shortly, thereafter a number of studies demonstrated that NAA was present in high concentrations in certain cancer cells, including breast and lung cancer, but not in the surrounding normal tissues Terunuma et al.

Higher NAT8L expression in other cancers melanoma, renal cell, breast, colon, and uterine also was associated with overall worse survival. Silencing of NAT8L reduced cancer cell viability and proliferation in vitro in multiple cancer cell lines. This effect was reversed by addition of exogenous NAA. In orthotopic mouse models of melanoma and ovarian cancer, NAT8L silencing reduced cancer growth.

NAA has also been shown to play a role in lung cancer Lou et al. In a study by Wynn et al. Using metabolic assays, including 13 C tracer experiments, it was found that SUM cells, the primary in vitro model of IBC, exhibit metabolic abnormalities including increased glutamine uptake and synthesis of NAA. These cells showed low TCA cycle activity from glucose and very low citrate synthesis from labeled pyruvate.

When NAA synthesis was examined, the mass labeled NAA was not derived from labeled glucose, but rather was derived from labeled glutamine. RhoC knockdown reduced glutamine consumption and NAA levels. We hypothesize that the connection between glutamine and NAA synthesis in IBC cells may be associated with the Warburg effect aerobic glycolysis and may contribute to the rapid proliferative behavior of IBC cells.

A study involving non-targeted stable isotope labeling and metabolic analysis showed that metabolic flux changes occurred in response to decreased oxygen availability in human adrenocarcinoma cells, leading to an increased glutamine contribution to acetyl-CoA production Weindl et al.

The source of acetyl-CoA for protein acetylation, including histone acetylation, has been assumed to be citrate exported from mitochondria, but acetyl-CoA derived from acetate via ACSS2 has been implicated as an alternative source Takahashi et al. Chen et al. The acetylation was specific for ACSS2, indicating that ACSS2 forms part of the transcription factor complex, and thus the acetyl-CoA derived from free acetate would be distinct from the acetyl-CoA formed from citrate reviewed in Jaworski et al.

Figure 4. Hypothesized role of NAA in cancer cells as an alternative source of acetyl-CoA for specific transcription factor acetylation in place of citrate.

This general mechanism could be involved in a number of transcription factor signaling pathways. See figure and text for additional details. Figure adapted from Jaworski et al. Figure 5. High NAA levels inhibit ACLY activity in brown adipose tissue, and this may turn out to be a more general phenomenon in other cell types including oligodendrocytes and certain types of cancer cells. When this pathway is activated in the cell nucleus, it can affect the activity of select transcription factors and modulate transcriptional activity.

Figure 6. NAA as a selective, alternative cytoplasmic and nuclear acetyl-CoA source. Reduced citrate synthase activity in cancer cells may result in increased NAA synthesis and export from mitochondria.

Citrate red pathway and NAA blue pathway are synthesized from acetyl-CoA in cancer cell mitochondria. Both citrate and NAA are exported from mitochondria to the cytoplasm. The transporter that moves NAA out of the mitochondrial matrix is not known, but the most likely candidate is the dicarboxylate transporter DIC. Citrate is converted in the cytoplasm into acetyl-CoA, which can then be used for lipid synthesis as well as protein acetylation reactions in the cytoplasm and nucleus.

NAA represents an alternative pathway that may allow for transport of acetate groups out of mitochondria, especially under hypoxic conditions when citrate synthase activity is reduced.

The portion of the citric acid cycle between citrate and alpha ketoglutarate is reduced gray lines , and the enzyme aspartate aminotransferase supplies alpha-ketoglutarate from glutamine via glutamate glutaminolysis. This may represent a salvage pathway for delivering acetyl-CoA from cancer cell mitochondria under hypoxic conditions, when citric acid cycle and citrate synthase activities are reduced. Recently, NAA has been shown to have actions in the nucleus, whereby it alters histone H3 methylation status, providing further evidence that NAA may be involved in chromatin remodeling associated with gene transcription Singhal et al.

We propose that NAA provides a unique source of acetate for intrinsic acetyl-CoA production within transcription factor complexes, especially in certain cancer cells, where oxidative phosphorylation and citrate production are often reduced.

Studies by Prokesch et al. Because citrate and NAA are both export products of mitochondrial metabolism, this type of cross-inhibitory mechanism would greatly favor NAA synthesis and export over that of citrate when NAA levels were high and ASPA activity was low. The same studies demonstrated several additional aspects of increased NAA levels including reduced expression of transcription factors associated with brown adipocyte differentiation Prokesch et al.

It is unclear if these effects of NAA on protein expression and histone acetylation are specific to adipose cells or if they pertain to other cell types including cancer cells. However, mounting evidence suggests that some of the effects of excessive NAA concentrations may impact the function of many cell types, especially cancer cells. If the effects of high NAA levels are found to be direct in some proteins, then certain core metabolic enzymes may have regulatory binding sites for NAA that modulate protein function.

It is also possible that NAA could directly affect other key regulatory enzymes such as HDACs, which would then impact histone acetylation levels directly. However, in brown adipocytes, Prokesch et al.

They noted that the effect appeared to be direct, rather than through acetyl-CoA, because cytoplasmic acetyl-CoA levels in NAA-supplemented cells were unchanged. The opposite effects on histone acetylation levels in different cell types could be due to the expression of different HDACs in oligodendrocytes and brown adipocytes, which could be differentially sensitive to high concentrations of NAA. This is a potentially fruitful research topic that could lead to discoveries about the links between NAA signaling and altered cell behavior in some cancers.

In this hypothesis, stromal cells e. The stromal cells employ glycolysis and produce lactate and other substrates including ketone bodies and pass these to the epithelial cancer cells, which utilize them for oxidative phosphorylation Martinez-Outschoorn et al.

It is thought that the epithelial cancer cells secrete reactive oxygen species, which drives autophagy and glycolysis in the stromal fibroblasts Pavlides et al. In this scenario, the tumor fibroblasts exhibit the Warburg effect and excrete energy-deriving metabolites, whereas the epithelial cancer cells employ the reverse Warburg effect and utilize these energy substrates for oxidative phosphorylation.

It is not clear what cell types produce and release NAA in different cancers, but it is likely that the cellular source of NAA varies between tumor types, dependent upon the cells of origin and the specific metabolic reprograming involved in oncogenesis in those cell types. If the NAA is released by cancer cells and is taken up by neighboring cancer or stromal cells for metabolism, then NAA would be an energy-deriving metabolite that did not fit the reverse Warburg effect role.

It is noteworthy that the related dipeptide, N-acetylaspartylglutamate NAAG , which is synthesized enzymatically from NAA and glutamate, has also been linked to cancer cell proliferation Long et al. In this situation, NAA acts very similar to the citrate system as a method of transferring an acetyl-CoA product to the cytoplasm, where acetyl-CoA can then be regenerated.

In the nervous system, a more complicated system evolved, wherein the synthetic NAT8L and degradative ASPA compartments were largely segregated into different cellular populations. The NAA derived acetate liberated in oligodendrocytes can go on to participate in lipid synthesis or protein acetylation reactions. In this expanded role including intercellular transport, NAA takes on a new role that is trophic in nature Moffett et al. It is in this new role that NAA may play a significant role in the progression of some cancers.

If excess NAA promotes growth and inhibits differentiation in other cell types, as it does in the case of glioma stem-like cells Long et al.

Sustained NAA synthesis in the absence of sufficient ASPA activity would lead to increasing intracellular levels, and this could help drive proliferation while also inhibiting differentiation.

However, this is clearly not a universal effect of NAA on cells. Mazzoccoli et al. This implies that NAA has opposing signaling functions in neuroblastoma and glioma stem-like cells. As such, NAA has signaling functions that lead neural-derived cell lines to differentiate but cause astrocyte-derived cell lines to proliferate.

These types of opposing effects in distinct cell types are consistent with NAA having a role in modulating cell behavior through the action at specific transcription factor complexes. The data are also consistent with selective activation of enzymes and receptors though targeted acetylation.

It is not known if NAA also has direct signaling activity through receptors, but to date, no receptor has been confirmed to be activated by physiological levels of NAA. One earlier report that NAA activated G protein-coupled metabotropic glutamate receptors in hippocampal neurons Yan et al. Importantly, within 2 h of administering nM NAA to MIN6 mouse insulinoma cells in culture, glucose stimulated insulin secretion was significantly reduced Hofer et al.

This effect on insulin secretion is too rapid to involve gene transcription, strongly suggesting that NAA has other signaling functions related to energy homeostasis. Further, MIN6 cells are of pancreatic origin, indicating that NAA has signaling functions outside the nervous system and adipose tissues. The mechanisms whereby NAA can influence energy derivation clearly involve mitochondrial metabolism and links to the TCA cycle, but effects on insulin secretion in target cells that do not synthesize NAA are more difficult to explain currently.

Based on investigations into Canavan disease, we have proposed that NAA may have direct signaling functions Appu et al. These could include activation or inhibition of enzymes, receptors, and other proteins via acetyl-transferase-mediated acetylation or direct actions at as yet unidentified receptors. In summary, the NAA signaling pathway has several arms including 1 local chromatin remodeling through selective histone acetylation via acetyl-CoA and acetyltransferases such as p, 2 transcriptional effects through acetylation of specific transcription factors via acetyl-CoA, and 3 direct action of NAA on as yet unidentified protein targets, possibly including enzymes as in the case of ACLY, as well as uncharacterized receptors.

While the NAA signaling pathway that we have proposed is hypothetical, it can explain how NAA-derived acetate affects gene transcription. Whether this pathway operates in organ systems other than the nervous system and adipose tissue also remains to be determined. But the role this pathway appears to play in many cancers suggests that the NAA pathway may be involved in regulation of transcription in a number of different tissues in response to physiological stress.

Acetate has received substantial attention as a prominent source of acetyl-CoA for cancer biomass accumulation. Acetate has been shown to promote cancer cell proliferation Kamphorst et al. However, the effects of exogenously supplied acetate or acetate precursors on cancer cells have provided conflicting results depending upon factors such as the cancer cell type and the molecular source of the acetate.

As noted in the previous section, NAA provides a unique source of acetate that promotes growth in some cancer cell types and inhibits growth in others. GTA has been found to have actions on cancer cell growth that are distinct in some respects to the effects of acetate alone reviewed in Jaworski et al. GTA was found to induce cytostatic G 0 growth arrest of oligodendroglioma and astrocytoma derived cells in vitro , without affecting the growth of normal cells Long et al.

Sodium acetate, at doses comparable to that generated by complete GTA hydrolysis, also promoted growth arrest. Interestingly, whereas the short-chain triglyceride GTA induced growth arrest, long-chain triglycerides promoted cell growth emphasizing that fatty acid chain length can have profound effects on cancer cell behavior. In another study, acetate supplementation maintained ATP levels in glucose-deprived melanoma cells in culture, whereas other short-chain fatty acids did not Lakhter et al.

GTA treatment induced G 0 growth arrest in most oligodendroglioma-derived and glioblastoma-derived glioma stem-like cells, but increased growth of neural stem cells Tsen et al. Additionally, GTA was found to enhance the efficacy of the chemotherapeutic agent temozolomide in orthotopically engrafted glioblastoma and oligodendroglioma-derived glioma stem-like cells Tsen et al.

Indeed, the effects of GTA on cell growth in some cell lines were found to be dependent on what tissue culture media the cells were grown in. These findings show that acetate does not invariably support tumor cell growth, but rather, depending upon the cell type and nutrient conditions, acetate can enhance cancer cell growth, or inhibit it.

The complexity of acetate metabolism and signaling functions in modulating cancer cell behavior have only been touched upon and discoveries with therapeutic potential are sure to follow. From an evolutionary perspective, we speculate that the dual nature of ACSS2 as both a lipogenic enzyme and a regulator of stress responses, including response to nutrient deprivation, may in part be an adaptation to irregular food availability. But under ketogenic conditions when food supplies are absent, ACSS2 shifts to a regulatory role to induce fatty acid oxidation and autophagy, thus helping maintain energy homeostasis.

ACSS2 also functions in a regulatory fashion after other stressors including injury, hypoxia, and infection. This regulatory system may be disrupted in certain cancers, wherein ACSS2 functions abnormally to promote lipid synthesis and stress related functions, including autophagy, simultaneously.

Because the role of ACSS2 is strongly dependent on cell type, its roles in the development of various cancers will be heterogeneous. Results in one type of cancer may not hold in other types, making generalizations difficult. Acetate supplementation may find therapeutic potential in obesity, insulin resistance, diabetes, blood loss, neuroinflammation, the treatment of certain mitochondrial diseases, and as a chemotherapeutic adjuvant for specific types of cancer.

In cell nuclei, ACSS2 may be associated with an array of transcription factor complexes that enable cells to respond to hypoxia, stress, nutrient deprivation, infection, and injury, as well as other adaptive responses including memory formation. Evidence points to ACSS2 acting to modulate transcription of select genes through acetylation of selective histones and transcription factors.

By directly supplying acetyl-CoA locally within the nucleus, ACSS2 acts as a transcription enhancer at select promoter regions. Acetate derived from nuclear deacetylation reactions is thus recycled by ACSS2 at active transcription sites, placing ACSS2 at a central point in acetylation-based transcriptional regulation.

It is also likely that ACSS2 can modulate the activity of many other targets including enzymes, transporters, receptors, cytoskeletal proteins, etc. NAA, as a unique source of acetate and acetyl-CoA distinct from citrate, is also associated with acetate-based transcriptional regulation in certain cell types, and in many cancers. We have presented a number of testable hypotheses including; do any central metabolic or other enzymes, for example, HDACs, have regulatory NAA binding sites that modulate their activity?

If so, does it operate in tissues other than the nervous system and adipose tissue? This could be tested in several ways, for example, by determining how much NAA-derived acetate ends up bound to transcription factors and histone proteins.

It would be especially important to test this in cells under physiological stress and in various cancer cell lines under conditions of hypoxia and nutrient limitation. Understanding the mechanisms by which the NAA-ASPA-ACSS2 pathway may act to selectively regulate transcription and other cellular functions associated with acetylation will expand our knowledge of normal and neoplastic metabolic reprograming.

Acetate, long discounted in human biology, is now garnering much needed attention for its roles in normal, pathological, and neoplastic cellular physiology. JM and AN conceived the project, all authors wrote the manuscripts.

All authors contributed to the article and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This two-part review only touched on the subject of acetate in mammalian and human biology, and we would like to acknowledge the vast literature on this subject and apologize to those whose contributions were not discussed directly.

The opinions and assertions expressed herein are those of the authors and do not necessarily reflect the official policy or position of the Uniformed Services University or the Department of Defense.

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The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. Lipid Res. Elshaghabee, F. Ethanol production by selected intestinal microorganisms and lactic acid bacteria growing under different nutritional conditions. In the field of organic chemistry the abbreviation Ac refers to the acetyl group.

Ac is also the symbol for the chemical element actinium , but confusion between actinium and the acetyl group is rare, since actinium has virtually no role in organic chemistry. Categories: Acetates Carboxylate anions. Read what you need to know about our industry portal chemeurope. My watch list my. My watch list My saved searches My saved topics My newsletter Register free of charge. Keep logged in. Cookies deactivated. To use all functions of this page, please activate cookies in your browser.

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