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ATP-citrate lyase

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https://www.readbyqxmd.com/read/28230778/caffeic-acid-expands-anti-tumor-effect-of-metformin-in-human-metastatic-cervical-carcinoma-htb-34-cells-implications-of-ampk-activation-and-impairment-of-fatty-acids-de-novo-biosynthesis
#1
Malgorzata Tyszka-Czochara, Pawel Konieczny, Marcin Majka
The efficacy of cancer treatments is often limited and associated with substantial toxicity. Appropriate combination of drug targeting specific mechanisms may regulate metabolism of tumor cells to reduce cancer cell growth and to improve survival. Therefore, we investigated the effects of anti-diabetic drug Metformin (Met) and a natural compound caffeic acid (trans-3,4-dihydroxycinnamic acid, CA) alone and in combination to treat an aggressive metastatic human cervical HTB-34 (ATCC CRL-1550) cancer cell line...
February 21, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28167750/acss2-mediated-acetyl-coa-synthesis-from-acetate-is-necessary-for-human-cytomegalovirus-infection
#2
Anna Vysochan, Arjun Sengupta, Aalim M Weljie, James C Alwine, Yongjun Yu
Recent studies have shown that human cytomegalovirus (HCMV) can induce a robust increase in lipid synthesis which is critical for the success of infection. In mammalian cells the central precursor for lipid biosynthesis, cytosolic acetyl CoA (Ac-CoA), is produced by ATP-citrate lyase (ACLY) from mitochondria-derived citrate or by acetyl-CoA synthetase short-chain family member 2 (ACSS2) from acetate. It has been reported that ACLY is the primary enzyme involved in making cytosolic Ac-CoA in cells with abundant nutrients...
February 6, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28153881/prevention-of-diet-induced-metabolic-dysregulation-inflammation-and-atherosclerosis-in-ldlr-mice-by-treatment-with-the-atp-citrate-lyase-inhibitor-bempedoic-acid
#3
Joshua P Samsoondar, Amy C Burke, Brian G Sutherland, Dawn E Telford, Cynthia G Sawyez, Jane Y Edwards, Stephen L Pinkosky, Roger S Newton, Murray W Huff
OBJECTIVE: Bempedoic acid (ETC-1002, 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid) is a novel low-density lipoprotein cholesterol-lowering compound. In animals, bempedoic acid targets the liver where it inhibits cholesterol and fatty acid synthesis through inhibition of ATP-citrate lyase and through activation of AMP-activated protein kinase. In this study, we tested the hypothesis that bempedoic acid would prevent diet-induced metabolic dysregulation, inflammation, and atherosclerosis...
February 2, 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28129980/discovery-of-furan-carboxylate-derivatives-as-novel-inhibitors-of-atp-citrate-lyase-via-virtual-high-throughput-screening
#4
Finith E Jernigan, Jun-Ichi Hanai, Vikas P Sukhatme, Lijun Sun
The enzyme ATP citrate lyase (ACL) catalyzes the formation of cytosolic acetyl CoA, the starting material for de novo lipid and cholesterol biosynthesis. The dysfunction and upregulation of ACL in numerous cancers makes it an attractive target for developing anticancer therapies. ACL inhibition by shRNA knockdown limits cancer cell proliferation and reduces cancer stemness. We designed and implemented a dual docking protocol to select virtual ACL inhibitors that were scored among the top 10 percentiles by both the Autodock Vina and the Glamdock algorithms...
January 16, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28106122/comparative-genomics-and-transcriptome-analysis-of-aspergillus-niger-and-metabolic-engineering-for-citrate-production
#5
Xian Yin, Hyun-Dong Shin, Jianghua Li, Guocheng Du, Long Liu, Jian Chen
Despite a long and successful history of citrate production in Aspergillus niger, the molecular mechanism of citrate accumulation is only partially understood. In this study, we used comparative genomics and transcriptome analysis of citrate-producing strains-namely, A. niger H915-1 (citrate titer: 157 g L(-1)), A1 (117 g L(-1)), and L2 (76 g L(-1))-to gain a genome-wide view of the mechanism of citrate accumulation. Compared with A. niger A1 and L2, A. niger H915-1 contained 92 mutated genes, including a succinate-semialdehyde dehydrogenase in the γ-aminobutyric acid shunt pathway and an aconitase family protein involved in citrate synthesis...
January 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28078050/complete-genome-sequence-of-lutibacter-profundi-lp1-t-isolated-from-an-arctic-deep-sea-hydrothermal-vent-system
#6
Juliane Wissuwa, Sven Le Moine Bauer, Ida Helene Steen, Runar Stokke
Lutibacter profundi LP1(T) within the family Flavobacteriaceae was isolated from a biofilm growing on the surface of a black smoker chimney at the Loki's Castle vent field, located on the Arctic Mid-Ocean Ridge. The complete genome of L. profundi LP1(T) is the first genome to be published within the genus Lutibacter. L. profundi LP1(T) consists of a single 2,966,978 bp circular chromosome with a GC content of 29.8%. The genome comprises 2,537 protein-coding genes, 40 tRNA species and 2 rRNA operons. The microaerophilic, organotrophic isolate contains genes for all central carbohydrate metabolic pathways...
2017: Standards in Genomic Sciences
https://www.readbyqxmd.com/read/28077572/impact-of-a-high-fat-diet-on-tissue-acyl-coa-and-histone-acetylation-levels
#7
Alessandro Carrer, Joshua L D Parris, Sophie Trefely, Ryan A Henry, David C Montgomery, AnnMarie Torres, John M Viola, Yin-Ming Kuo, Ian A Blair, Jordan L Meier, Andrew J Andrews, Nathaniel W Snyder, Kathryn E Wellen
Cellular metabolism dynamically regulates the epigenome via availability of the metabolite substrates of chromatin-modifying enzymes. The impact of diet on the metabolism-epigenome axis is poorly understood but could alter gene expression and influence metabolic health. ATP citrate-lyase produces acetyl-CoA in the nucleus and cytosol and regulates histone acetylation levels in many cell types. Consumption of a high-fat diet (HFD) results in suppression of ATP citrate-lyase levels in tissues such as adipose and liver, but the impact of diet on acetyl-CoA and histone acetylation in these tissues remains unknown...
February 24, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28059952/atp-citrate-lyase-genetics-molecular-biology-and-therapeutic-target-for-dyslipidemia
#8
Amy C Burke, Murray W Huff
PURPOSE OF REVIEW: ATP-citrate lyase (ACLY) has re-emerged as a drug target for LDL cholesterol (LDL-C) lowering. We review ACLY as a therapeutic strategy, its genetics, its molecular and cellular biology, and also its inhibition. RECENT FINDINGS: ACLY is a critical enzyme linking glucose catabolism to lipogenesis by providing acetyl-CoA from mitochondrial citrate for fatty acid and cholesterol biosynthesis. Human genetic variants have been associated with enhanced growth and survival of several cancers, and with attenuated plasma triglyceride responses to dietary fish oil...
January 5, 2017: Current Opinion in Lipidology
https://www.readbyqxmd.com/read/28018484/mechanistic-insights-into-the-effect-of-imidazolium-ionic-liquid-on-lipid-production-by-geotrichum-fermentans
#9
Li-Ping Liu, Min-Hua Zong, Robert J Linhardt, Wen-Yong Lou, Ning Li, Chao Huang, Hong Wu
BACKGROUND: Ionic liquid (IL) pretreatment has emerged as a promising technique that enables complete utilization of lignocellulosic biomass for biofuel production. However, imidazolium IL has recently been shown to exhibit inhibitory effect on cell growth and product formation of industrial microbes, such as oleaginous microorganisms. To date, the mechanism of this inhibition remains largely unknown. RESULTS: In this study, the feasibility of [Bmim][OAc]-pretreated rice straw hydrolysate as a substrate for microbial lipid production by Geotrichum fermentans, also known as Trichosporon fermentans, was evaluated...
2016: Biotechnology for Biofuels
https://www.readbyqxmd.com/read/28018404/functional-and-integrative-analysis-of-the-proteomic-profile-of-radish-root-under-pb-exposure
#10
Yan Wang, Liang Xu, Mingjia Tang, Haiyan Jiang, Wei Chen, Wei Zhang, Ronghua Wang, Liwang Liu
Lead (Pb) is one of the most abundant heavy metal (HM) pollutants, which can penetrate the plant through the root and then enter the food chain causing potential health risks for human beings. Radish is an important root vegetable crop worldwide. To investigate the mechanism underlying plant response to Pb stress in radish, the protein profile changes of radish roots respectively upon Pb(NO3)2 at 500 mg L(-1)(Pb500) and 1000 mg L(-1)(Pb1000), were comprehensively analyzed using iTRAQ (Isobaric Tag for Relative and Absolute Quantification)...
2016: Frontiers in Plant Science
https://www.readbyqxmd.com/read/27997879/design-and-synthesis-of-emodin-derivatives-as-novel-inhibitors-of-atp-citrate-lyase
#11
Steffi K Koerner, Jun-Ichi Hanai, Sha Bai, Finith E Jernigan, Miwa Oki, Chieko Komaba, Emi Shuto, Vikas P Sukhatme, Lijun Sun
Aberrant cellular metabolism drives cancer proliferation and metastasis. ATP citrate lyase (ACL) plays a critical role in generating cytosolic acetyl CoA, a key building block for de novo fatty acid and cholesterol biosynthesis. ACL is overexpressed in cancer cells, and siRNA knockdown of ACL limits cancer cell proliferation and reduces cancer stemness. We characterized a new class of ACL inhibitors bearing the key structural feature of the natural product emodin. Structure-activity relationship (SAR) study led to the identification of 1d as a potent lead that demonstrated dose-dependent inhibition of proliferation and cancer stemness of the A549 lung cancer cell line...
January 27, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27892461/liver-specific-atp-citrate-lyase-inhibition-by-bempedoic-acid-decreases-ldl-c-and-attenuates-atherosclerosis
#12
Stephen L Pinkosky, Roger S Newton, Emily A Day, Rebecca J Ford, Sarka Lhotak, Richard C Austin, Carolyn M Birch, Brennan K Smith, Sergey Filippov, Pieter H E Groot, Gregory R Steinberg, Narendra D Lalwani
Despite widespread use of statins to reduce low-density lipoprotein cholesterol (LDL-C) and associated atherosclerotic cardiovascular risk, many patients do not achieve sufficient LDL-C lowering due to muscle-related side effects, indicating novel treatment strategies are required. Bempedoic acid (ETC-1002) is a small molecule intended to lower LDL-C in hypercholesterolemic patients, and has been previously shown to modulate both ATP-citrate lyase (ACL) and AMP-activated protein kinase (AMPK) activity in rodents...
November 28, 2016: Nature Communications
https://www.readbyqxmd.com/read/27892457/amplification-of-usp13-drives-ovarian-cancer-metabolism
#13
Cecil Han, Lifeng Yang, Hyun Ho Choi, Joelle Baddour, Abhinav Achreja, Yunhua Liu, Yujing Li, Jiada Li, Guohui Wan, Cheng Huang, Guang Ji, Xinna Zhang, Deepak Nagrath, Xiongbin Lu
Dysregulated energetic metabolism has been recently identified as a hallmark of cancer. Although mutations in metabolic enzymes hardwire metabolism to tumourigenesis, they are relatively infrequent in ovarian cancer. More often, cancer metabolism is re-engineered by altered abundance and activity of the metabolic enzymes. Here we identify ubiquitin-specific peptidase 13 (USP13) as a master regulator that drives ovarian cancer metabolism. USP13 specifically deubiquitinates and thus upregulates ATP citrate lyase and oxoglutarate dehydrogenase, two key enzymes that determine mitochondrial respiration, glutaminolysis and fatty acid synthesis...
November 28, 2016: Nature Communications
https://www.readbyqxmd.com/read/27811979/a-combination-of-genome-wide-association-and-transcriptome-analysis-reveals-candidate-genes-controlling-harvest-index-related-traits-in-brassica-napus
#14
Kun Lu, Zhongchun Xiao, Hongju Jian, Liu Peng, Cunmin Qu, Minglian Fu, Bin He, Linmei Tie, Ying Liang, Xingfu Xu, Jiana Li
Harvest index (HI), the ratio of seed mass to total biomass of the aboveground plant parts, is an important trait for harvestable yield of crops. Unfortunately, HI of Brassica napus is lower than that of other economically important crops. To identify candidate genes associated with high HI, a genome-wide association study of HI and four HI-related traits was conducted with 520 B. napus accessions cultivated in both Yunnan and Chongqing. We detected 294 single nucleotide polymorphisms significantly associated with the abovementioned traits, including 79 SNPs that affected two or more traits...
November 4, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27761435/-13-c-metabolic-flux-analysis-for-systematic-metabolic-engineering-of-s-cerevisiae-for-overproduction-of-fatty-acids
#15
Amit Ghosh, David Ando, Jennifer Gin, Weerawat Runguphan, Charles Denby, George Wang, Edward E K Baidoo, Chris Shymansky, Jay D Keasling, Héctor García Martín
Efficient redirection of microbial metabolism into the abundant production of desired bioproducts remains non-trivial. Here, we used flux-based modeling approaches to improve yields of fatty acids in Saccharomyces cerevisiae. We combined (13)C labeling data with comprehensive genome-scale models to shed light onto microbial metabolism and improve metabolic engineering efforts. We concentrated on studying the balance of acetyl-CoA, a precursor metabolite for the biosynthesis of fatty acids. A genome-wide acetyl-CoA balance study showed ATP citrate lyase from Yarrowia lipolytica as a robust source of cytoplasmic acetyl-CoA and malate synthase as a desirable target for downregulation in terms of acetyl-CoA consumption...
2016: Frontiers in Bioengineering and Biotechnology
https://www.readbyqxmd.com/read/27760311/atp-citrate-lyase-controls-a-glucose-to-acetate-metabolic-switch
#16
Steven Zhao, AnnMarie Torres, Ryan A Henry, Sophie Trefely, Martina Wallace, Joyce V Lee, Alessandro Carrer, Arjun Sengupta, Sydney L Campbell, Yin-Ming Kuo, Alexander J Frey, Noah Meurs, John M Viola, Ian A Blair, Aalim M Weljie, Christian M Metallo, Nathaniel W Snyder, Andrew J Andrews, Kathryn E Wellen
Mechanisms of metabolic flexibility enable cells to survive under stressful conditions and can thwart therapeutic responses. Acetyl-coenzyme A (CoA) plays central roles in energy production, lipid metabolism, and epigenomic modifications. Here, we show that, upon genetic deletion of Acly, the gene coding for ATP-citrate lyase (ACLY), cells remain viable and proliferate, although at an impaired rate. In the absence of ACLY, cells upregulate ACSS2 and utilize exogenous acetate to provide acetyl-CoA for de novo lipogenesis (DNL) and histone acetylation...
October 18, 2016: Cell Reports
https://www.readbyqxmd.com/read/27689010/knockdown-of-atp-citrate-lyase-in-pancreatic-beta-cells-does-not-inhibit-insulin-secretion-or-glucose-flux-and-implicates-the-acetoacetate-pathway-in-insulin-secretion
#17
Mahmoud El Azzouny, Melissa J Longacre, Israr-Ul H Ansari, Robert T Kennedy, Charles F Burant, Michael J MacDonald
OBJECTIVE: Glucose-stimulated insulin secretion in pancreatic beta cells requires metabolic signals including the generation of glucose-derived short chain acyl-CoAs in the cytosol from mitochondrially-derived metabolites. One concept of insulin secretion is that ATP citrate lyase generates short chain acyl-CoAs in the cytosol from mitochondrially-derived citrate. Of these, malonyl-CoA, is believed to be an important signal in insulin secretion. Malonyl-CoA is also a precursor for lipids...
October 2016: Molecular Metabolism
https://www.readbyqxmd.com/read/27686035/lipogenesis-in-a-wing-polymorphic-cricket-canalization-versus-morph-specific-plasticity-as-a-function-of-nutritional-heterogeneity
#18
Anthony J Zera, Rebecca Clark, Spence Behmer
The influence of variable nutritional input on life history adaptation is a central, but incompletely understood aspect of life history physiology. The wing-polymorphic cricket, Gryllus firmus, has been extensively studied with respect to the biochemical basis of life history adaptation, in particular, modification of lipid metabolism that underlies the enhanced accumulation of lipid flight fuel in the dispersing morph [LW(f)=long wings with functional flight muscles] relative to the flightless (SW=short-winged) morph...
December 2016: Journal of Insect Physiology
https://www.readbyqxmd.com/read/27664236/cullin3-klhl25-ubiquitin-ligase-targets-acly-for-degradation-to-inhibit-lipid-synthesis-and-tumor-progression
#19
Cen Zhang, Juan Liu, Grace Huang, Yuhan Zhao, Xuetian Yue, Hao Wu, Jun Li, Junlan Zhu, Zhiyuan Shen, Bruce G Haffty, Wenwei Hu, Zhaohui Feng
Increased lipid synthesis is a key characteristic of many cancers that is critical for cancer progression. ATP-citrate lyase (ACLY), a key enzyme for lipid synthesis, is frequently overexpressed or activated in cancer to promote lipid synthesis and tumor progression. Cullin3 (CUL3), a core protein for the CUL3-RING ubiquitin ligase complex, has been reported to be a tumor suppressor and frequently down-regulated in lung cancer. Here, we found that CUL3 interacts with ACLY through its adaptor protein, KLHL25 (Kelch-like family member 25), to ubiquitinate and degrade ACLY in cells...
September 1, 2016: Genes & Development
https://www.readbyqxmd.com/read/27663902/bempedoic-acid-etc-1002-an-investigational-inhibitor-of-atp-citrate-lyase
#20
REVIEW
Ozlem Bilen, Christie M Ballantyne
Bempedoic acid (ETC-1002), a novel therapeutic approach for low-density lipoprotein cholesterol (LDL-C) lowering, inhibits ATP citrate lyase (ACL), an enzyme involved in fatty acid and cholesterol synthesis. Although rodent studies suggested potential effects of ACL inhibition on both fatty acid and cholesterol synthesis, studies in humans show an effect only on cholesterol synthesis. In phase 2 studies, ETC-1002 reduced LDL-C as monotherapy, combined with ezetimibe, and added to statin therapy, with LDL-C lowering most pronounced when ETC-1002 was combined with ezetimibe in patients who cannot tolerate statins...
October 2016: Current Atherosclerosis Reports
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