Tricarballylate and hydroxycitrate: Substrate and inhibitor of ATP: Citrate oxaloacetate lyase

Watson, John; Fang, Marie; Lowenstein, John M.

doi:10.1016/0003-9861(69)90532-3

Cited by 245 publications

(119 citation statements)

References 21 publications

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“…ACLY converts citrate into acetyl-CoA, a precursor for fatty acid and mevalonate synthesis pathways (6)(7)(8). Both of these pathways are associated with cancer cell growth and transformation (9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

ATP Citrate Lyase Knockdown Induces Growth Arrest and Apoptosis through Different Cell- and Environment-Dependent Mechanisms

Zaidi

Royaux

Swinnen

et al. 2012

Molecular Cancer Therapeutics

101

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ATP citrate lyase (ACLY) is a cytosolic enzyme that catalyzes generation of acetyl-CoA, which is a vital building block for fatty acid, cholesterol, and isoprenoid biosynthesis. ACLY is upregulated in several types of cancer, and its inhibition induces proliferation arrest in certain cancer cells. As ACLY is involved in several pathways, its downregulation may affect multiple processes. Here, we have shown that short hairpin RNAmediated ACLY silencing in cell lines derived from different types of cancers induces proliferation, cell-cycle arrest, and apoptosis. However, this antiproliferative effect of ACLY knockdown was observed only when cells were cultivated under lipid-reduced growth conditions. Proliferation arrest induced by ACLY silencing was partially rescued by supplementing the media with fatty acids and/or cholesterol. This indicates that the ACLY knockdown-mediated growth arrest might be the result of either fatty acid or cholesterol starvation or both. In the absence of ACLY, the cancer cells displayed elevated expression of sterol regulatory element binding protein-regulated downstream genes involved in de novo fatty acid and cholesterol biosynthesis. Furthermore, ACLY suppression resulted in elevated expression of acyl-CoA synthetase short-chain family member 2 (ACSS2), an enzyme that also produces acetyl-CoA using acetate as a substrate. Acetate supplementation partially rescued the cancer cells from ACLY suppression-induced proliferation arrest. We also observed that the absence of ACLY enhanced ACSS2-dependent lipid synthesis. These findings provide new insights into the role of ACLY in cancer cell growth and give critical information about the effects of ACLY silencing on different pathways. This information is crucial in understanding the possible application of ACLY inhibition in cancer therapeutics. Mol Cancer Ther; 11(9); 1925-35. Ó2012 AACR.

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Section: Introductionmentioning

confidence: 99%

ATP Citrate Lyase Knockdown Induces Growth Arrest and Apoptosis through Different Cell- and Environment-Dependent Mechanisms

Zaidi

Royaux

Swinnen

et al. 2012

Molecular Cancer Therapeutics

101

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“…Using a new gas chromatography-mass spectrometry technique (21), we showed that [ 13 C]oleate contributes carbon to the acetyl moiety of malonyl-CoA (16). Also, experiments with hydroxycitrate, an inhibitor of ATP-citrate lyase (22), support an at least partial role of citrate as a precursor of the acetyl moiety of malonyl-CoA in the heart (16) and in muscle (15).…”

mentioning

confidence: 98%

Peroxisomal Fatty Acid Oxidation Is a Substantial Source of the Acetyl Moiety of Malonyl-CoA in Rat Heart

Reszko

Kasumov

Jobbins

et al. 2004

Journal of Biological Chemistry

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Little is known about the sources of acetyl-CoA used for the synthesis of malonyl-CoA, a key regulator of mitochondrial fatty acid oxidation in the heart. In perfused rat hearts, we previously showed that malonylCoA is labeled from both carbohydrates and fatty acids. This study was aimed at assessing the mechanisms of incorporation of fatty acid carbons into malonyl-CoA. Rat hearts were perfused with glucose, lactate, pyruvate, and a fatty acid (palmitate, oleate or docosanoate). In each experiment, substrates were 13 C-labeled to yield singly or/and doubly labeled acetyl-CoA. The mass isotopomer distribution of malonyl-CoA was compared with that of the acetyl moiety of citrate, which reflects mitochondrial acetyl-CoA. In the presence of labeled glucose or lactate/pyruvate, the 13 C labeling of malonylCoA was up to 2-fold lower than that of mitochondrial acetyl-CoA. However, in the presence of a fatty acid labeled in its first acetyl moiety, the 13 C labeling of malonyl-CoA was up to 10-fold higher than that of mitochondrial acetyl-CoA. The labeling of malonyl-CoA and of the acetyl moiety of citrate is compatible with peroxisomal ␤-oxidation forming C 12 and C 14 acyl-CoAs and contributing >50% of the fatty acid-derived acetyl groups that end up in malonyl-CoA. This fraction increases with the fatty acid chain length. By supplying acetyl-CoA for malonyl-CoA synthesis, peroxisomal ␤-oxidation may participate in the control of mitochondrial fatty acid oxidation in the heart. In addition, this pathway may supply some acyl groups used in protein acylation, which is increasingly recognized as an important regulatory mechanism for many biochemical processes.Malonyl-CoA is an intermediate of fatty acid synthesis in lipogenic organs. It is also a key regulator of mitochondrial long-chain fatty acid oxidation in most mammalian tissues because it modulates the activity of carnitine palmitoyltransferase-I (1-4). Malonyl-CoA is formed by cytosolic acetyl-CoA carboxylase (ACC) 1 and is disposed off either by lipogenesis or via malonyl-CoA decarboxylase, which reforms acetyl-CoA. Alterations in malonyl-CoA metabolism and regulation have been associated with insulin resistance and obesity (5). Mice lacking ACC␤, the predominant ACC isoform in cardiac and skeletal muscle, show not only decreased malonyl-CoA levels and increased fatty acid oxidation but also major alterations in systemic energy balance with decreased body fat despite increased food intake (6). The above data emphasize the crucial role of malonyl-CoA in fat metabolism and energy balance. In the heart, much work has been conducted on the control of malonyl-CoA metabolism, emphasizing the mechanisms of regulation of ACC␤ and malonyl-CoA decarboxylase. This includes acute changes in activity through phosphorylation via cAMPdependent protein kinase or AMP kinase (for recent reviews, see Refs. 5 and 7-10), as well as chronic regulation through gene expression involving peroxisomal proliferator-activated receptor (11,12). However, little is known about the origin of ac...

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“…Citrate can be exported from the mitochondria via the malate-citrate shuttle system and used as a substrate for ATP-citrate lyase (ACLY) (13,27,28). ACLY catalyzes the formation of acetyl-CoA and oxaloacetate from cytosolic citrate and coenzyme A in the presence of ATP (27)(28)(29). ACLY therefore serves as a cross-link between glucose metabolism and the fatty acid and mevalonate synthetic pathways.…”

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confidence: 99%

Glucose-dependent de Novo Lipogenesis in B Lymphocytes

Dufort

Gumina

et al. 2014

Journal of Biological Chemistry

146

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Background:The metabolic requirements underlying B lymphocyte differentiation are poorly understood. Results: Differentiation is accompanied by glucose metabolism into fatty acid and cholesterol synthesis, mediated by ATPcitrate lyase (ACLY). Conclusion: ACLY-dependent lipogenesis is required for several phenotypic changes defining plasma cell differentiation. Significance: This study proposes a critical role for ACLY coupled glucose-dependent de novo lipogenesis in LPS-induced B lymphocyte differentiation.

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Tricarballylate and hydroxycitrate: Substrate and inhibitor of ATP: Citrate oxaloacetate lyase

Cited by 245 publications

References 21 publications

ATP Citrate Lyase Knockdown Induces Growth Arrest and Apoptosis through Different Cell- and Environment-Dependent Mechanisms

ATP Citrate Lyase Knockdown Induces Growth Arrest and Apoptosis through Different Cell- and Environment-Dependent Mechanisms

Peroxisomal Fatty Acid Oxidation Is a Substantial Source of the Acetyl Moiety of Malonyl-CoA in Rat Heart

Glucose-dependent de Novo Lipogenesis in B Lymphocytes

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