scholarly journals The central role of acetyl-CoA in plant metabolism, as examined through studies of ATP citrate lyase and the bio1 mutant of Arabidopsis

2004 ◽  
Author(s):  
Elizabeth K. Winters
Keyword(s):  
Plant Metabolism ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Citrate Lyase

Probing the link between citrate and malonyl-CoA in perfused rat hearts

2002 ◽  
Vol 283 (4) ◽  
pp. H1379-H1386 ◽  
Author(s):  
Myriame Poirier ◽  
Geneviève Vincent ◽  
Aneta E. Reszko ◽  
Bertrand Bouchard ◽  
Joanne K. Kelleher ◽  
...  
Keyword(s):  
Carbon Sources ◽  
Acid Oxidation ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Rat Hearts ◽  
Citrate Lyase ◽  
Malonyl Coa ◽  
Perfused Rat Hearts ◽  
Citrate Release

Little is known about the sources of cytosolic acetyl-CoA used for the synthesis of malonyl-CoA, a key regulator of fatty acid oxidation in the heart. We tested the hypothesis that citrate provides acetyl-CoA for malonyl-CoA synthesis after its mitochondrial efflux and cleavage by cytosolic ATP-citrate lyase. We expanded on a previous study where we characterized citrate release from perfused rat hearts (Vincent G, Comte B, Poirier M, and Des Rosiers C. Citrate release by perfused rat hearts: a window on mitochondrial cataplerosis. Am J Physiol Endocrinol Metab 278: E846–E856, 2000). In the present study, we show that citrate release rates, ranging from 6 to 22 nmol/min, can support a net increase in malonyl-CoA concentrations induced by changes in substrate supply, at most 0.7 nmol/min. In experiments with [U-13C](lactate + pyruvate) and [1-13C]oleate, we show that the acetyl moiety of malonyl-CoA is derived from both pyruvate and long-chain fatty acids. This 13C-labeling of malonyl-CoA occurred without any changes in its concentration. Hydroxycitrate, an inhibitor of ATP-citrate lyase, prevents increases in malonyl-CoA concentrations and decreases its labeling from [U-13C](lactate + pyruvate). Our data support at least a partial role of citrate in the transfer from the mitochondria to cytosol of acetyl units for malonyl-CoA synthesis. In addition, they provide a dynamic picture of malonyl-CoA metabolism: even when the malonyl-CoA concentration remains constant, there appears to be a constant need to supply acetyl-CoA from various carbon sources, both carbohydrates and lipids, for malonyl-CoA synthesis.

scholarly journals Changes in the activity of citrate lyase, malic enzyme and acetyl-CoA synthetase in rat liver after short-term and long-term feeding with ethanol

1973 ◽  
Vol 29 (2) ◽  
pp. 307-316 ◽  
Author(s):  
E. Fellenius ◽  
U. Nisbeth ◽  
L. Pilström ◽  
K.-H. Kiessling
Keyword(s):  
Malic Enzyme ◽  
Liquid Diet ◽  
Short Term ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Pronounced Increase ◽  
Ethanol Group ◽  
Citrate Lyase

1. The effect of short-term and long-term feeding (0–80 d) with a liquid diet containing ethanol on the activity of rat hepatic enzymes related to lipogenesis has been evaluated. Carbohydrates were isoenergetically substituted for ethanol in the control animals.2. The maximum concentration of triglycerides in the livers was reached after about 30 d, when it was almost three times as high as in the control animals. The activity of malic enzyme (EC 1·1·1·40) and ATP citrate lyase (EC 4·1·3·8) decreased significantly in the ethanol group, compared with the control rats, within 10 d and remained low during the rest of the experiment (80 d). After 20 d, the acetyl-CoA synthetase (EC 6·2·1·1) activity increased significantly in the livers of the ethanol-fed rats but fell subsequently to values similar to those in the livers of the control rats. Thus, despite a pronounced increase in the amount of triglyceride in the livers of rats on a liquid diet containing ethanol, there was a dramatic decrease in the activity of the enzymes (malic enzyme and citrate lyase) involved in lipogenesis.3. The almost unchanged activity of acetyl-CoA synthetase shows that the utilization of acetate, produced when ethanol is oxidized, is not stimulated by long-term feeding with ethanol. The involvement of citrate lyase in various postulated shuttles for the transport of reducing equivalents across the mitochondrial membrane and the role of malic enzyme in the microsomal ethanol-oxidizing system are discussed.

scholarly journals Comparative Metabolites and Citrate-Degrading Enzymes Activities in Citrus Fruits Reveal the Role of Balance between ACL and Cyt-ACO in Metabolite Conversions

Plants ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 350 ◽  
Author(s):  
Lingxia Guo ◽  
Yongzhong Liu ◽  
Lijuan Luo ◽  
Syed Bilal Hussain ◽  
Yingxin Bai ◽  
...  
Keyword(s):  
Carbon Flux ◽  
Acid Metabolism ◽  
Soluble Sugars ◽  
Citrus Fruits ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Degrading Enzymes ◽  
Citrate Lyase ◽  
Fruit Development And Ripening

Citric acid metabolism is considered to be the central cellular process of metabolite conversions. ATP-citrate lyase (ACL) and cytosolic aconitase (cyt-ACO) are the two citrate-degrading enzymes that decide the carbon flux towards different metabolite biosynthesis pathways. However, the correlation of their activities with metabolite concentrations in citrus fruits is still unclear. Here, the concentrations of soluble sugars, organic acids, acetyl-CoA, flavonoids, carotenoids, and γ-aminobutyric acid, as well as the activities of ACL, cyt-ACO, acetyl-CoA C-acetyltransferase, and acetyl-CoA carboxylase, were compared among the fruits of six citrus cultivars during fruit development and ripening. The results showed that the correlation between citrate concentration and cyt-ACO or ACL activity varied greatly among cultivars, while the activities of cyt-ACO and ACL had a significantly negative correlation (r = −0.4431). Moreover, ACL overexpression and RNA interference in the Citrus callus indicated that increasing and decreasing the ACL activity could reduce and induce cyt-ACO activity, respectively. In addition, significant correlation was only observed between the ACL activity and the concentration of acetyl-CoA (r = 0.4333). Taken together, the present study suggested that ACL and cyt-ACO synergistically control the citrate fate for the biosynthesis of other metabolites, but they are not the key determinants for the accumulation of citrate, as well as other metabolites in citrus fruits.

scholarly journals Exploring the Role of ATP-Citrate Lyase in the Immune System

2021 ◽  
Vol 12 ◽  
Author(s):  
Monica Dominguez ◽  
Bernhard Brüne ◽  
Dmitry Namgaladze
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Histone Acetylation ◽  
Epigenetic Regulation ◽  
De Novo ◽  
Regulation Of Gene Expression ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Citrate Lyase

Studies over the past decade have revealed that metabolism profoundly influences immune responses. In particular, metabolism causes epigenetic regulation of gene expression, as a growing number of metabolic intermediates are substrates for histone post-translational modifications altering chromatin structure. One of these substrates is acetyl-coenzyme A (CoA), which donates an acetyl group for histone acetylation. Cytosolic acetyl-CoA is also a critical substrate for de novo synthesis of fatty acids and sterols necessary for rapid cellular growth. One of the main enzymes catalyzing cytosolic acetyl-CoA formation is ATP-citrate lyase (ACLY). In addition to its classical function in the provision of acetyl-CoA for de novo lipogenesis, ACLY contributes to epigenetic regulation through histone acetylation, which is increasingly appreciated. In this review we explore the current knowledge of ACLY and acetyl-CoA in mediating innate and adaptive immune responses. We focus on the role of ACLY in supporting de novo lipogenesis in immune cells as well as on its impact on epigenetic alterations. Moreover, we summarize alternative sources of acetyl-CoA and their contribution to metabolic and epigenetic regulation in cells of the immune system.

Acetyl-CoA is produced by the citrate synthase homology module of ATP-citrate lyase

2021 ◽  
Author(s):  
Kenneth Verstraete ◽  
Koen H. G. Verschueren ◽  
Ann Dansercoer ◽  
Savvas N. Savvides
Keyword(s):  
Citrate Synthase ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Citrate Lyase ◽  
Homology Module

The role of ATP citrate lyase in the transfer of acetyl groups in rat liver

1968 ◽  
Vol 158 (1) ◽  
pp. 51-61 ◽  
Author(s):  
Yasushi Daikuhara ◽  
Takuo Tsunemi ◽  
Yoshiro Takeda
Keyword(s):  
Rat Liver ◽  
Atp Citrate Lyase ◽  
Citrate Lyase

Abstract 15978: Acetyl-coa Catalysis by Atp-citrate Lyase is Essential for Myofibroblast Differentiation and Persistence

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Michael P Lazaropoulos ◽  
Andrew A Gibb ◽  
Anh Huynh ◽  
Kathryn Wellen ◽  
John W Elrod
Keyword(s):  
Histone Acetylation ◽  
Transcriptional Activation ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Metabolic Reprogramming ◽  
Myofibroblast Differentiation ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Matrix Deposition ◽  
Citrate Lyase

A feature of heart failure (HF) is excessive extracellular matrix deposition and cardiac remodeling by a differentiated fibroblast population known as myofibroblasts. Identifying mechanisms of myofibroblast differentiation in cardiac fibrosis could yield novel therapeutic targets to delay or reverse HF. Recent evidence suggests that myofibroblast differentiation requires metabolic reprogramming for transcriptional activation of the myofibroblast gene program by chromatin-dependent mechanisms. We previously reported that inhibition of histone demethylation blocks myofibroblast formation, however, whether histone acetylation (e.g., H3K27ac, a prominent mark associated with gene transcription) is involved in fibroblast reprogramming remains unclear. ATP-citrate lyase (ACLY) synthesizes acetyl-CoA and therein supplies acetyl-CoA to the nucleus, where it is used as a substrate by histone acetyltransferases (HATs). To define the role of acetyl-CoA metabolism in myofibroblast differentiation, we stimulated differentiation in mouse embryonic fibroblasts (MEFs) and adult mouse cardiac fibroblasts (ACFs) with the pro-fibrotic agonist transforming growth factor β (TGFβ) and treated cells with a pharmacological inhibitor of ACLY. ACLY inhibition decreased myofibroblast gene expression in ACF and MEFs in TGFβ-stimulated myofibroblast differentiation, in addition to decreasing the population of αSMA positive MEFs. Genetic deletion of ACLY in MEFs recapitulated the results observed with pharmacological inhibition. Encouragingly, the ACLY inhibitor was sufficient to revert fully differentiated myofibroblasts under continuous TGFβ stimulation to a quiescent, non-fibrotic phenotype. Altogether, our data indicate that ACLY activity is necessary for myofibroblast differentiation and persistence. We hypothesize that ACLY-dependent acetyl-CoA synthesis is necessary for histone acetylation and transcriptional activation of the myofibroblast gene program. Currently, we are examining mechanisms of ACLY-dependent chromatin remodeling in fibroblasts and the in vivo relevance of this mechanism in mutant mice. In summary, ACLY is a potential target to reverse cardiac fibrosis and lessen HF.

scholarly journals RNA-seq reveals novel mechanistic targets of withaferin A in prostate cancer cells

2020 ◽  
Vol 41 (6) ◽  
pp. 778-789 ◽  
Author(s):  
Su-Hyeong Kim ◽  
Eun-Ryeong Hahm ◽  
Krishna B Singh ◽  
Sruti Shiva ◽  
Jacob Stewart-Ornstein ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Acid Synthesis ◽  
Acetyl Coa Carboxylase ◽  
Rna Seq ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Citrate Lyase

Abstract Withaferin A (WA) is a promising phytochemical exhibiting in vitro and in vivo anticancer activities against prostate and other cancers, but the mechanism of its action is not fully understood. In this study, we performed RNA-seq analysis using 22Rv1 human prostate cancer cell line to identify mechanistic targets of WA. Kyoto Encyclopedia of Genes and Genomes pathway analysis of the differentially expressed genes showed most significant enrichment of genes associated with metabolism. These results were validated using LNCaP and 22Rv1 human prostate cancer cells and Hi-Myc transgenic mice as models. The intracellular levels of acetyl-CoA, total free fatty acids and neutral lipids were decreased significantly following WA treatment in both cells, which was accompanied by downregulation of mRNA (confirmed by quantitative reverse transcription-polymerase chain reaction) and protein levels of key fatty acid synthesis enzymes, including ATP citrate lyase, acetyl-CoA carboxylase 1, fatty acid synthase and carnitine palmitoyltransferase 1A. Ectopic expression of c-Myc, but not constitutively active Akt, conferred a marked protection against WA-mediated suppression of acetyl-CoA carboxylase 1 and fatty acid synthase protein expression, and clonogenic cell survival. WA was a superior inhibitor of cell proliferation and fatty acid synthesis in comparison with known modulators of fatty acid metabolism including cerulenin and etomoxir. Intraperitoneal WA administration to Hi-Myc transgenic mice (0.1 mg/mouse, three times/week for 5 weeks) also resulted in a significant decrease in circulating levels of total free fatty acids and phospholipids, and expression of ATP citrate lyase, acetyl-CoA carboxylase 1, fatty acid synthase and carnitine palmitoyltransferase 1A proteins in the prostate in vivo.

scholarly journals ATP-citrate lyase is essential for high glucose-induced histone hyperacetylation and fibrogenic gene upregulation in mesangial cells

2017 ◽  
Vol 313 (2) ◽  
pp. F423-F429 ◽  
Author(s):  
Dilip K. Deb ◽  
Yinyin Chen ◽  
Jian Sun ◽  
Youli Wang ◽  
Yan Chun Li
Keyword(s):  
Histone Acetylation ◽  
High Glucose ◽  
Mesangial Cells ◽  
Nuclear Accumulation ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Ecm Proteins ◽  
Histone Hyperacetylation ◽  
Citrate Lyase ◽  
Tgf Β1

The goal of this study was to address the role of ATP-citrate lyase (ACL), an enzyme that converts citrate to acetyl-CoA, in high glucose (HG)-induced histone acetylation and profibrotic gene expression. Our recent ChIP-Seq studies have demonstrated that HG induces genome-wide histone hyperacetylation in mesangial cells (MCs). Here, we showed that exposure of MCs to HG markedly increased histone acetylation at the H3K9/14 and H3K18 marks and induced the expression of potent profibrotic factors TGF-β1, TGF-β3, and connective tissue growth factor (CTGF). The induction of these profibrotic factors was further enhanced by histone deacetylase inhibitor but suppressed by histone acetyl-transferase inhibitor, confirming the importance of histone acetylation in this regulation. Interestingly, HG not only upregulated ACL expression but also promoted ACL nuclear translocation, evidenced by increased ACL concentration and activity in the nuclear extracts. Consistent with this observation, transfection of MCs with a plasmid-carrying green fluorescent protein (GFP)-ACL fusion protein led to GFP nuclear accumulation when cultured in HG condition. Silencing ACL with siRNAs alleviated HG-induced histone hyperacetylation, as well as upregulation of TGF-β1, TGF-β3, CTGF, and extracellular matrix (ECM) proteins fibronectin and collagen type IV, whereas ACL overexpression further enhanced HG induction of histone acetylation, as well as these profibrotic factors and ECM proteins. Collectively, these observations demonstrate that HG promotes ACL expression and translocation into the nucleus, where ACL converts citrate to acetyl-CoA to provide the substrate for histone acetylation, leading to upregulation of fibrogenic genes. Therefore, ACL plays a critical role in epigenetic regulation of diabetic renal fibrosis.

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