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Pesquisa : D08.811.913.050.331 [Categoria DeCS]
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[PMID]:29235331
[Au] Autor:Zagayko AL; Shkapo AI; Fylymonenko VP; Briukhanova TO
[Ti] Título:The impact of hydroxycitric acid on the lipid metabolism profile under experimental insulin resistance syndrome of Syrian hamsters.
[So] Source:Ukr Biochem J;88(3):78-82, 2016 May-Jun.
[Is] ISSN:2409-4943
[Cp] País de publicação:Ukraine
[La] Idioma:eng
[Ab] Resumo:The syndrome of insulin resistance (IR) is one of the leading reasons for the increased risk of cardiovascular diseases and their complications. Among the key components of IR are obesity and dyslipidemia. Hydroxycitric acid (HCA), an inhibitor of a key enzyme of lipogenesis ATP citrate lyase (ACLY) is a promising obesity treatment agent. The aim of this work was to investigate the effect of HCA on lipid and lipoproteins content in the blood serum, as well as lipid content and activity of some lipid metabolism enzymes in the liver of hamsters with IR. IR was modeled by keeping animals on high-fat diet with addition of fructose. Lipid content was determined by using standard reagent kits, the level of lipoproteins, the activity of glucose 6-phosphate dehydrogenase and ACLY ­ spectrophotometrically, lysosomal lipase activity ­ fluorimetrically. Development of hyperlipidemia and atherogenic dyslipidemia, lipid accumulation in the liver, activation of lysosomal lipase and ACLY and reduction of glucose 6-phosphate dehydrogenase activity were shown under IR. The treatment by HCA reduces the manifestations of hyperlipidemia, but enhances the lipid accumulation in the liver.
[Mh] Termos MeSH primário: Fármacos Antiobesidade/farmacologia
Citratos/farmacologia
Hiperlipidemias/tratamento farmacológico
Resistência à Insulina
Fígado/efeitos dos fármacos
Obesidade/tratamento farmacológico
[Mh] Termos MeSH secundário: ATP Citrato (pro-S)-Liase/antagonistas & inibidores
ATP Citrato (pro-S)-Liase/genética
ATP Citrato (pro-S)-Liase/metabolismo
Animais
Dieta Hiperlipídica/efeitos adversos
Frutose/efeitos adversos
Regulação da Expressão Gênica
Glucosefosfato Desidrogenase/genética
Glucosefosfato Desidrogenase/metabolismo
Hiperlipidemias/enzimologia
Hiperlipidemias/etiologia
Hiperlipidemias/patologia
Lipase/genética
Lipase/metabolismo
Metabolismo dos Lipídeos/efeitos dos fármacos
Fígado/enzimologia
Fígado/patologia
Lisossomos/efeitos dos fármacos
Lisossomos/enzimologia
Masculino
Mesocricetus
Obesidade/enzimologia
Obesidade/etiologia
Obesidade/patologia
Oxirredução
Síndrome
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Obesity Agents); 0 (Citrates); 30237-26-4 (Fructose); 8W94T9026R (hydroxycitric acid); EC 1.1.1.49 (Glucosephosphate Dehydrogenase); EC 2.3.3.8 (ATP Citrate (pro-S)-Lyase); EC 3.1.1.3 (Lipase)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180116
[Lr] Data última revisão:
180116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171214
[St] Status:MEDLINE
[do] DOI:10.15407/ubj88.03.078


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[PMID]:28407230
[Au] Autor:Xu H; Luo J; Ma G; Zhang X; Yao D; Li M; Loor JJ
[Ad] Endereço:Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, P. R. China.
[Ti] Título:Acyl-CoA synthetase short-chain family member 2 (ACSS2) is regulated by SREBP-1 and plays a role in fatty acid synthesis in caprine mammary epithelial cells.
[So] Source:J Cell Physiol;233(2):1005-1016, 2018 Feb.
[Is] ISSN:1097-4652
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Sterol regulatory element binding protein 1 (SREBP-1) is well-known as the master regulator of lipogenesis in rodents. Acyl-CoA synthetase short-chain family member 2 (ACSS2) plays a key role in lipogenesis by synthesizing acetyl-CoA from acetate for lipogenesis. ATP citrate lyase (ACLY) catalyzes the conversion of citrate and coenzyme A to acetyl-CoA, hence, it is also important for lipogenesis. Although ACSS2 function in cancer cells has been elucidated, its essentiality in ruminant mammary lipogenesis is unknown. Furthermore, ACSS2 gene promoter and its regulatory mechanisms have not known. Expression of ACSS2 was high in lipid synthesizing tissues, and its expression increased during lactation compared with non-lactating period. Simultaneous knockdown of both ACSS2 and ACLY by siRNA in primary goat mammary epithelial cells decreased (p < 0.05) the mRNA abundance of genes associated with de novo fatty acid synthesis (FASN, ACACA, SCD1) and triacylglycerol (TAG) synthesis (DGAT1, DGAT2, GPAM, and AGPAT6). Genes responsible for lipid droplet formation and secretion (PLIN2 and PLIN3) and fatty acid oxidation (ATGL, HSL, ACOX, and CPT1A) all decreased (p < 0.05) after ACSS2 and ACLY knockdown. Total cellular TAG content and lipid droplet formation also decreased. Use of a luciferase reporter assay revealed a direct regulation of ACSS2 by SREBP-1. Furthermore, SREBP-1 interacted with an SRE (SREBP response element) spanning at -475 to -483 bp on the ACSS2 promoter. Taken together, our results revealed a novel pathway that SREBP-1 may regulate fatty acid and TAG synthesis by regulating the expression of ACSS2.
[Mh] Termos MeSH primário: Acetato-CoA Ligase/metabolismo
Células Epiteliais/enzimologia
Ácidos Graxos/biossíntese
Lactação
Glândulas Mamárias Animais/enzimologia
Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
[Mh] Termos MeSH secundário: ATP Citrato (pro-S)-Liase/genética
ATP Citrato (pro-S)-Liase/metabolismo
Acetato-CoA Ligase/genética
Animais
Células Cultivadas
Feminino
Regulação Enzimológica da Expressão Gênica
Cabras
Gotículas Lipídicas/metabolismo
Lipogênese/genética
Glândulas Mamárias Animais/citologia
Mutagênese Sítio-Dirigida
Mutação
Regiões Promotoras Genéticas
Interferência de RNA
Elemento de Resposta Sérica
Proteína de Ligação a Elemento Regulador de Esterol 1/genética
Transfecção
Triglicerídeos/biossíntese
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fatty Acids); 0 (Sterol Regulatory Element Binding Protein 1); 0 (Triglycerides); EC 2.3.3.8 (ATP Citrate (pro-S)-Lyase); EC 6.2.1.1 (Acetate-CoA Ligase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171128
[Lr] Data última revisão:
171128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170414
[St] Status:MEDLINE
[do] DOI:10.1002/jcp.25954


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[PMID]:28777081
[Au] Autor:Hu J; Komakula A; Fraser ME
[Ad] Endereço:Department of Biological Sciences, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 1N4, Canada.
[Ti] Título:Binding of hydroxycitrate to human ATP-citrate lyase.
[So] Source:Acta Crystallogr D Struct Biol;73(Pt 8):660-671, 2017 Aug 01.
[Is] ISSN:2059-7983
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Hydroxycitrate from the fruit of Garcinia cambogia [i.e. (2S,3S)-2-hydroxycitrate] is the best-known inhibitor of ATP-citrate lyase. Well diffracting crystals showing how the inhibitor binds to human ATP-citrate lyase were grown by modifying the protein. The protein was modified by introducing cleavage sites for Tobacco etch virus protease on either side of a disordered linker. The protein crystallized consisted of residues 2-425-ENLYFQ and S-488-810 of human ATP-citrate lyase. (2S,3S)-2-Hydroxycitrate binds in the same orientation as citrate, but the citrate-binding domain (residues 248-421) adopts a different orientation with respect to the rest of the protein (residues 4-247, 490-746 and 748-809) from that previously seen. For the first time, electron density was evident for the loop that contains His760, which is phosphorylated as part of the catalytic mechanism. The pro-S carboxylate of (2S,3S)-2-hydroxycitrate is available to accept a phosphoryl group from His760. However, when co-crystals were grown with ATP and magnesium ions as well as either the inhibitor or citrate, Mg -ADP was bound and His760 was phosphorylated. The phosphoryl group was not transferred to the organic acid. This led to the interpretation that the active site is trapped in an open conformation. The strategy of designing cleavage sites to remove disordered residues could be useful in determining the crystal structures of other proteins.
[Mh] Termos MeSH primário: ATP Citrato (pro-S)-Liase/química
ATP Citrato (pro-S)-Liase/metabolismo
Citratos/metabolismo
[Mh] Termos MeSH secundário: Sítios de Ligação
Domínio Catalítico
Citratos/química
Cristalografia por Raios X
Frutas/química
Frutas/metabolismo
Garcinia cambogia/química
Garcinia cambogia/metabolismo
Seres Humanos
Magnésio/química
Magnésio/metabolismo
Simulação de Acoplamento Molecular
Ligação Proteica
Domínios Proteicos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Citrates); 8W94T9026R (hydroxycitric acid); EC 2.3.3.8 (ATP Citrate (pro-S)-Lyase); I38ZP9992A (Magnesium)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170805
[St] Status:MEDLINE
[do] DOI:10.1107/S2059798317009871


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[PMID]:28689661
[Au] Autor:Sivanand S; Rhoades S; Jiang Q; Lee JV; Benci J; Zhang J; Yuan S; Viney I; Zhao S; Carrer A; Bennett MJ; Minn AJ; Weljie AM; Greenberg RA; Wellen KE
[Ad] Endereço:Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
[Ti] Título:Nuclear Acetyl-CoA Production by ACLY Promotes Homologous Recombination.
[So] Source:Mol Cell;67(2):252-265.e6, 2017 Jul 20.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:While maintaining the integrity of the genome and sustaining bioenergetics are both fundamental functions of the cell, potential crosstalk between metabolic and DNA repair pathways is poorly understood. Since histone acetylation plays important roles in DNA repair and is sensitive to the availability of acetyl coenzyme A (acetyl-CoA), we investigated a role for metabolic regulation of histone acetylation during the DNA damage response. In this study, we report that nuclear ATP-citrate lyase (ACLY) is phosphorylated at S455 downstream of ataxia telangiectasia mutated (ATM) and AKT following DNA damage. ACLY facilitates histone acetylation at double-strand break (DSB) sites, impairing 53BP1 localization and enabling BRCA1 recruitment and DNA repair by homologous recombination. ACLY phosphorylation and nuclear localization are necessary for its role in promoting BRCA1 recruitment. Upon PARP inhibition, ACLY silencing promotes genomic instability and cell death. Thus, the spatial and temporal control of acetyl-CoA production by ACLY participates in the mechanism of DNA repair pathway choice.
[Mh] Termos MeSH primário: ATP Citrato (pro-S)-Liase/metabolismo
Acetilcoenzima A/metabolismo
Proteína BRCA1/metabolismo
Núcleo Celular/enzimologia
Quebras de DNA de Cadeia Dupla
Reparo de DNA por Recombinação
[Mh] Termos MeSH secundário: Células A549
ATP Citrato (pro-S)-Liase/genética
Acetilação
Animais
Proteína BRCA1/genética
Núcleo Celular/efeitos dos fármacos
Feminino
Pontos de Checagem da Fase G2 do Ciclo Celular
Instabilidade Genômica
Glucose/metabolismo
Células HCT116
Células HeLa
Histonas/metabolismo
Seres Humanos
Melanoma Experimental/enzimologia
Melanoma Experimental/genética
Melanoma Experimental/patologia
Camundongos Endogâmicos C57BL
Fosforilação
Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia
Ligação Proteica
Processamento de Proteína Pós-Traducional
Interferência de RNA
Reparo de DNA por Recombinação/efeitos dos fármacos
Pontos de Checagem da Fase S do Ciclo Celular
Serina
Fatores de Tempo
Transfecção
Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BRCA1 Protein); 0 (BRCA1 protein, human); 0 (Histones); 0 (Poly(ADP-ribose) Polymerase Inhibitors); 0 (TP53BP1 protein, human); 0 (Tumor Suppressor p53-Binding Protein 1); 452VLY9402 (Serine); 72-89-9 (Acetyl Coenzyme A); EC 2.3.3.8 (ATP Citrate (pro-S)-Lyase); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170711
[St] Status:MEDLINE


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[PMID]:28490526
[Au] Autor:Deb DK; Chen Y; Sun J; Wang Y; Li YC
[Ad] Endereço:Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, Illinois.
[Ti] Título:ATP-citrate lyase is essential for high glucose-induced histone hyperacetylation and fibrogenic gene upregulation in mesangial cells.
[So] Source:Am J Physiol Renal Physiol;313(2):F423-F429, 2017 Aug 01.
[Is] ISSN:1522-1466
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo: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-ß1, TGF-ß3, 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-ß1, TGF-ß3, 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.
[Mh] Termos MeSH primário: ATP Citrato (pro-S)-Liase/metabolismo
Nefropatias Diabéticas/enzimologia
Epigênese Genética/efeitos dos fármacos
Glucose/toxicidade
Histonas/genética
Células Mesangiais/efeitos dos fármacos
Processamento de Proteína Pós-Traducional/efeitos dos fármacos
[Mh] Termos MeSH secundário: ATP Citrato (pro-S)-Liase/genética
Acetilcoenzima A/metabolismo
Acetilação
Transporte Ativo do Núcleo Celular
Animais
Linhagem Celular Transformada
Ácido Cítrico/metabolismo
Colágeno Tipo IV/genética
Colágeno Tipo IV/metabolismo
Fator de Crescimento do Tecido Conjuntivo/genética
Fator de Crescimento do Tecido Conjuntivo/metabolismo
Nefropatias Diabéticas/genética
Nefropatias Diabéticas/patologia
Fibronectinas/genética
Fibronectinas/metabolismo
Fibrose
Células Mesangiais/enzimologia
Células Mesangiais/patologia
Camundongos
Interferência de RNA
Fatores de Tempo
Transfecção
Fator de Crescimento Transformador beta1/genética
Fator de Crescimento Transformador beta1/metabolismo
Fator de Crescimento Transformador beta3/genética
Fator de Crescimento Transformador beta3/metabolismo
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Collagen Type IV); 0 (Ctgf protein, mouse); 0 (Fibronectins); 0 (Histones); 0 (Tgfb1 protein, mouse); 0 (Tgfb3 protein, mouse); 0 (Transforming Growth Factor beta1); 0 (Transforming Growth Factor beta3); 139568-91-5 (Connective Tissue Growth Factor); 2968PHW8QP (Citric Acid); 72-89-9 (Acetyl Coenzyme A); EC 2.3.3.8 (ATP Citrate (pro-S)-Lyase); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170918
[Lr] Data última revisão:
170918
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170512
[St] Status:MEDLINE
[do] DOI:10.1152/ajprenal.00029.2017


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[PMID]:28443474
[Au] Autor:Wang D; Yin L; Wei J; Yang Z; Jiang G
[Ad] Endereço:1 Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China.
[Ti] Título:ATP citrate lyase is increased in human breast cancer, depletion of which promotes apoptosis.
[So] Source:Tumour Biol;39(4):1010428317698338, 2017 Apr.
[Is] ISSN:1423-0380
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Breast cancer is a malignant tumor that is harmful to women's health around the world. Investigating the biological mechanism is, therefore, of pivotal importance to improve patients' prognoses. Compared to non-neoplastic tissues, enhanced glucose and lipid metabolism is one of the most common properties of malignant breast cancer. Adenosine triphosphate (ATP) citrate lyase is a key enzyme linking aerobic glycolysis and fatty acid synthesis and is of high biological and prognostic significance in breast cancer. In our clinical study, fresh clinical tissues were used to analyze ATP citrate lyase expression by western blotting, and paraffin archived samples from 62 breast cancer patients were used to analyze ATP citrate lyase expression by immunohistochemistry. In the cellular study, following small interfering RNA-mediated inhibition of ATP citrate lyase in MCF-7 cells, cell viability and apoptosis were measured using the Cell Counting Kit-8 and flow cytometry, respectively. Breast cancer tissues showed strong expression of ATP citrate lyase, whereas adjacent normal tissues showed weak expression. Silencing of endogenous ATP citrate lyase expression by small interfering RNA in MCF-7 cells suppressed cell viability and increased cell apoptosis. Collectively, our study revealed that expression of ATP citrate lyase was significantly increased in breast cancer tissue compared with normal tissue. In addition, we found that depletion of ATP citrate lyase suppressed tumor growth, which suggests that ATP citrate lyase-related inhibitors might be potential therapeutic approaches for breast cancer.
[Mh] Termos MeSH primário: ATP Citrato (pro-S)-Liase/biossíntese
Apoptose/genética
Biomarcadores Tumorais/biossíntese
Neoplasias da Mama/genética
[Mh] Termos MeSH secundário: ATP Citrato (pro-S)-Liase/genética
Adulto
Biomarcadores Tumorais/genética
Neoplasias da Mama/patologia
Sobrevivência Celular/genética
Feminino
Regulação Neoplásica da Expressão Gênica
Seres Humanos
Metabolismo dos Lipídeos/genética
Células MCF-7
Meia-Idade
Prognóstico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); EC 2.3.3.8 (ATP Citrate (pro-S)-Lyase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170613
[Lr] Data última revisão:
170613
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170427
[St] Status:MEDLINE
[do] DOI:10.1177/1010428317698338


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[PMID]:28223367
[Au] Autor:Solomon LA; Podder S; He J; Jackson-Chornenki NL; Gibson K; Ziliotto RG; Rhee J; DeKoter RP
[Ad] Endereço:Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
[Ti] Título:Coordination of Myeloid Differentiation with Reduced Cell Cycle Progression by PU.1 Induction of MicroRNAs Targeting Cell Cycle Regulators and Lipid Anabolism.
[So] Source:Mol Cell Biol;37(10), 2017 May 15.
[Is] ISSN:1098-5549
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:During macrophage development, myeloid progenitor cells undergo terminal differentiation coordinated with reduced cell cycle progression. Differentiation of macrophages from myeloid progenitors is accompanied by increased expression of the E26 transformation-specific transcription factor PU.1. Reduced PU.1 expression leads to increased proliferation and impaired differentiation of myeloid progenitor cells. It is not understood how PU.1 coordinates macrophage differentiation with reduced cell cycle progression. In this study, we utilized cultured PU.1-inducible myeloid cells to perform genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) analysis coupled with gene expression analysis to determine targets of PU.1 that may be involved in regulating cell cycle progression. We found that genes encoding cell cycle regulators and enzymes involved in lipid anabolism were directly and inducibly bound by PU.1 although their steady-state mRNA transcript levels were reduced. Inhibition of lipid anabolism was sufficient to reduce cell cycle progression in these cells. Induction of PU.1 reduced expression of , an important activator of genes involved in cell cycle and lipid anabolism, indirectly through microRNA 223. Next-generation sequencing identified microRNAs validated as targeting cell cycle and lipid anabolism for downregulation. These results suggest that PU.1 coordinates cell cycle progression with differentiation through induction of microRNAs targeting cell cycle regulators and lipid anabolism.
[Mh] Termos MeSH primário: Ciclo Celular/fisiologia
Diferenciação Celular
Metabolismo dos Lipídeos
Células Mieloides/citologia
Proteínas Proto-Oncogênicas/metabolismo
Transativadores/metabolismo
[Mh] Termos MeSH secundário: ATP Citrato (pro-S)-Liase/metabolismo
Células Cultivadas
Fator de Transcrição E2F1/metabolismo
Regulação da Expressão Gênica
Seres Humanos
Metabolismo dos Lipídeos/genética
Macrófagos/citologia
Macrófagos/metabolismo
MicroRNAs
Células Mieloides/metabolismo
Proteínas Proto-Oncogênicas/genética
Transativadores/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (E2F1 Transcription Factor); 0 (MicroRNAs); 0 (Proto-Oncogene Proteins); 0 (Trans-Activators); 0 (proto-oncogene protein Spi-1); EC 2.3.3.8 (ATP Citrate (pro-S)-Lyase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171102
[Lr] Data última revisão:
171102
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170223
[St] Status:MEDLINE


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[PMID]:28153881
[Au] Autor:Samsoondar JP; Burke AC; Sutherland BG; Telford DE; Sawyez CG; Edwards JY; Pinkosky SL; Newton RS; Huff MW
[Ad] Endereço:From the Molecular Medicine Research Laboratory, Robarts Research Institute (J.P.S., A.C.B., B.G.S., D.E.T., C.G.S., J.Y.E., M.W.H.), Department of Biochemistry (J.P.S., A.C.B., M.W.H.), and Department of Medicine (D.E.T., C.G.S., J.Y.E., M.W.H.), The University of Western Ontario, London, Canada; a
[Ti] Título:Prevention of Diet-Induced Metabolic Dysregulation, Inflammation, and Atherosclerosis in Mice by Treatment With the ATP-Citrate Lyase Inhibitor Bempedoic Acid.
[So] Source:Arterioscler Thromb Vasc Biol;37(4):647-656, 2017 Apr.
[Is] ISSN:1524-4636
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo: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. APPROACH AND RESULTS: mice were fed a high-fat, high-cholesterol diet (42% kcal fat, 0.2% cholesterol) supplemented with bempedoic acid at 0, 3, 10 and 30 mg/kg body weight/day. Treatment for 12 weeks dose-dependently attenuated diet-induced hypercholesterolemia, hypertriglyceridemia, hyperglycemia, hyperinsulinemia, fatty liver and obesity. Compared to high-fat, high-cholesterol alone, the addition of bempedoic acid decreased plasma triglyceride (up to 64%) and cholesterol (up to 50%) concentrations, and improved glucose tolerance. Adiposity was significantly reduced with treatment. In liver, bempedoic acid prevented cholesterol and triglyceride accumulation, which was associated with increased fatty acid oxidation and reduced fatty acid synthesis. Hepatic gene expression analysis revealed that treatment significantly increased expression of genes involved in fatty acid oxidation while suppressing inflammatory gene expression. In full-length aorta, bempedoic acid markedly suppressed cholesteryl ester accumulation, attenuated the expression of proinflammatory M1 genes and attenuated the / ratio. Treatment robustly attenuated atherosclerotic lesion development in the aortic sinus by 44%, with beneficial changes in morphology, characteristic of earlier-stage lesions. CONCLUSIONS: Bempedoic acid effectively prevents plasma and tissue lipid elevations and attenuates the onset of inflammation, leading to the prevention of atherosclerotic lesion development in a mouse model of metabolic dysregulation.
[Mh] Termos MeSH primário: ATP Citrato (pro-S)-Liase/antagonistas & inibidores
Aterosclerose/prevenção & controle
Ácidos Dicarboxílicos/farmacologia
Dieta Hiperlipídica
Dislipidemias/prevenção & controle
Inibidores Enzimáticos/farmacologia
Ácidos Graxos/farmacologia
Inflamação/prevenção & controle
Fígado/efeitos dos fármacos
Obesidade/prevenção & controle
Receptores de LDL/deficiência
[Mh] Termos MeSH secundário: ATP Citrato (pro-S)-Liase/metabolismo
Animais
Aterosclerose/sangue
Aterosclerose/enzimologia
Aterosclerose/genética
Biomarcadores/sangue
Glicemia/efeitos dos fármacos
Glicemia/metabolismo
Modelos Animais de Doenças
Dislipidemias/sangue
Dislipidemias/enzimologia
Dislipidemias/genética
Regulação da Expressão Gênica
Predisposição Genética para Doença
Inflamação/sangue
Inflamação/enzimologia
Inflamação/genética
Mediadores da Inflamação/sangue
Insulina/sangue
Lipídeos/sangue
Fígado/enzimologia
Masculino
Camundongos Knockout
Obesidade/sangue
Obesidade/enzimologia
Obesidade/genética
Fenótipo
Receptores de LDL/genética
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Blood Glucose); 0 (Dicarboxylic Acids); 0 (Enzyme Inhibitors); 0 (Fatty Acids); 0 (Inflammation Mediators); 0 (Insulin); 0 (Lipids); 0 (Receptors, LDL); 1EJ6Z6Q368 (8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid); EC 2.3.3.8 (ATP Citrate (pro-S)-Lyase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170204
[St] Status:MEDLINE
[do] DOI:10.1161/ATVBAHA.116.308963


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[PMID]:28129980
[Au] Autor:Jernigan FE; Hanai JI; Sukhatme VP; Sun L
[Ad] Endereço:Center for Drug Discovery and Translational Research, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
[Ti] Título:Discovery of furan carboxylate derivatives as novel inhibitors of ATP-citrate lyase via virtual high-throughput screening.
[So] Source:Bioorg Med Chem Lett;27(4):929-935, 2017 Feb 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo: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. Via this in silico screens of a focused furoic acid library, we discovered four subtypes of furans and benzofurans as novel ACL inhibitors. The hit rate of our in silico protocol was 45.8% with 11 of 24 virtual hits confirmed as active in an in vitro ACL enzymatic assay. The IC of the most potent ACL inhibitor A1 is 4.1µM. Our results demonstrated remarkable hit rate by the dual docking approach and provided novel chemical scaffolds for the development of ACL inhibitors for the treatment of cancer.
[Mh] Termos MeSH primário: ATP Citrato (pro-S)-Liase/antagonistas & inibidores
Ácidos Carboxílicos/farmacologia
Inibidores Enzimáticos/farmacologia
Furanos/química
[Mh] Termos MeSH secundário: Ácidos Carboxílicos/química
Linhagem Celular
Descoberta de Drogas
Inibidores Enzimáticos/química
Ensaios de Triagem em Larga Escala
Seres Humanos
Simulação de Acoplamento Molecular
Estrutura Molecular
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carboxylic Acids); 0 (Enzyme Inhibitors); 0 (Furans); EC 2.3.3.8 (ATP Citrate (pro-S)-Lyase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170818
[Lr] Data última revisão:
170818
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170129
[St] Status:MEDLINE


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[PMID]:28077572
[Au] Autor:Carrer A; Parris JL; Trefely S; Henry RA; Montgomery DC; Torres A; Viola JM; Kuo YM; Blair IA; Meier JL; Andrews AJ; Snyder NW; Wellen KE
[Ad] Endereço:From the Department of Cancer Biology, Abramson Family Cancer Research Institute, and.
[Ti] Título:Impact of a High-fat Diet on Tissue Acyl-CoA and Histone Acetylation Levels.
[So] Source:J Biol Chem;292(8):3312-3322, 2017 Feb 24.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo: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. Here we examined the effects of HFD on levels of acyl-CoAs and histone acetylation in mouse white adipose tissue (WAT), liver, and pancreas. We report that mice consuming a HFD have reduced levels of acetyl-CoA and/or acetyl-CoA:CoA ratio in these tissues. In WAT and the pancreas, HFD also impacted the levels of histone acetylation; in particular, histone H3 lysine 23 acetylation was lower in HFD-fed mice. Genetic deletion of in cultured adipocytes also suppressed acetyl-CoA and histone acetylation levels. In the liver, no significant effects on histone acetylation were observed with a HFD despite lower acetyl-CoA levels. Intriguingly, acetylation of several histone lysines correlated with the acetyl-CoA: (iso)butyryl-CoA ratio in liver. Butyryl-CoA and isobutyryl-CoA interacted with the acetyltransferase P300/CBP-associated factor (PCAF) in liver lysates and inhibited its activity This study thus provides evidence that diet can impact tissue acyl-CoA and histone acetylation levels and that acetyl-CoA abundance correlates with acetylation of specific histone lysines in WAT but not in the liver.
[Mh] Termos MeSH primário: Acil Coenzima A/metabolismo
Tecido Adiposo/metabolismo
Dieta Hiperlipídica
Histonas/metabolismo
Fígado/metabolismo
[Mh] Termos MeSH secundário: ATP Citrato (pro-S)-Liase/genética
ATP Citrato (pro-S)-Liase/metabolismo
Acetilação
Acil Coenzima A/análise
Animais
Células Cultivadas
Dieta Hiperlipídica/efeitos adversos
Deleção de Genes
Histonas/análise
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Pâncreas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acyl Coenzyme A); 0 (Histones); EC 2.3.3.8 (ATP Citrate (pro-S)-Lyase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170113
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.750620



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