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[PMID]: 28669930 [Au] Autor: Ning T; Cui H; Sun F; Zou J [Ad] Endereço: Department of Neurosurgery, Weihai Central Hospital, Shandong, China. [Ti] Título: Systemic analysis of genome-wide expression profiles identified potential therapeutic targets of demethylation drugs for glioblastoma. [So] Source: Gene;627:387-392, 2017 Sep 05. [Is] ISSN: 1879-0038 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: Glioblastoma represents one of the most aggressive malignant brain tumors with high morbidity and motility. Demethylation drugs have been developed for its treatment with little efficacy has been observed. The purpose of this study was to screen therapeutic targets of demethylation drugs or bioactive molecules for glioblastoma through systemic bioinformatics analysis. We firstly downloaded genome-wide expression profiles from the Gene Expression Omnibus (GEO) and conducted the primary analysis through R software, mainly including preprocessing of raw microarray data, transformation between probe ID and gene symbol and identification of differential expression genes (DEGs). Secondly, functional enrichment analysis was conducted via the Database for Annotation, Visualization and Integrated Discovery (DAVID) to explore biological processes involved in the development of glioblastoma. Thirdly, we constructed protein-protein interaction (PPI) network of interested genes and conducted cross analysis for multi datasets to obtain potential therapeutic targets for glioblastoma. Finally, we further confirmed the therapeutic targets through real-time RT-PCR. As a result, biological processes that related to cancer development, amino metabolism, immune response and etc. were found to be significantly enriched in genes that differential expression in glioblastoma and regulated by 5'aza-dC. Besides, network and cross analysis identified ACAT2, UFC1 and CYB5R1 as novel therapeutic targets of demethylation drugs which also confirmed by real time RT-PCR. In conclusions, our study identified several biological processes and genes that involved in the development of glioblastoma and regulated by 5'aza-dC, which would be helpful for the treatment of glioblastoma. [Mh] Termos MeSH primário: Antineoplásicos/farmacologia Neoplasias Encefálicas/genética Metilação de DNA/efeitos dos fármacos Inibidores Enzimáticos/farmacologia Regulação Neoplásica da Expressão Gênica Glioblastoma/genética [Mh] Termos MeSH secundário: Citocromo-B(5) Redutase/genética Redes Reguladoras de Genes Genoma Humano Seres Humanos Mapas de Interação de Proteínas Esterol O-Aciltransferase/genética Enzimas de Conjugação de Ubiquitina/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Enzyme Inhibitors); 0 (UFC1 protein, human); EC 1.6.2.2 (Cytochrome-B(5) Reductase); EC 2.3.1.26 (Sterol O-Acyltransferase); EC 2.3.1.26 (sterol O-acyltransferase 2); EC 2.3.2.23 (Ubiquitin-Conjugating Enzymes) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170920 [Lr] Data última revisão: 170920 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170704 [St] Status: MEDLINE

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[PMID]: 28604676 [Au] Autor: Wang YJ; Bian Y; Luo J; Lu M; Xiong Y; Guo SY; Yin HY; Lin X; Li Q; Chang CCY; Chang TY; Li BL; Song BL [Ad] Endereço: The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China. [Ti] Título: Cholesterol and fatty acids regulate cysteine ubiquitylation of ACAT2 through competitive oxidation. [So] Source: Nat Cell Biol;19(7):808-819, 2017 Jul. [Is] ISSN: 1476-4679 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Ubiquitin linkage to cysteine is an unconventional modification targeting protein for degradation. However, the physiological regulation of cysteine ubiquitylation is still mysterious. Here we found that ACAT2, a cellular enzyme converting cholesterol and fatty acid to cholesteryl esters, was ubiquitylated on Cys277 for degradation when the lipid level was low. gp78-Insigs catalysed Lys48-linked polyubiquitylation on this Cys277. A high concentration of cholesterol and fatty acid, however, induced cellular reactive oxygen species (ROS) that oxidized Cys277, resulting in ACAT2 stabilization and subsequently elevated cholesteryl esters. Furthermore, ACAT2 knockout mice were more susceptible to high-fat diet-associated insulin resistance. By contrast, expression of a constitutively stable form of ACAT2 (C277A) resulted in higher insulin sensitivity. Together, these data indicate that lipid-induced stabilization of ACAT2 ameliorates lipotoxicity from excessive cholesterol and fatty acid. This unconventional cysteine ubiquitylation of ACAT2 constitutes an important mechanism for sensing lipid-overload-induced ROS and fine-tuning lipid homeostasis. [Mh] Termos MeSH primário: Colesterol/metabolismo Ácidos Graxos/metabolismo Fígado/enzimologia Esterol O-Aciltransferase/metabolismo [Mh] Termos MeSH secundário: Animais Células CHO Ésteres do Colesterol/metabolismo Cricetulus Cisteína Dieta Hiperlipídica Modelos Animais de Doenças Genótipo Células Hep G2 Homeostase Seres Humanos Resistência à Insulina Masculino Camundongos Endogâmicos C57BL Camundongos Knockout Oxirredução Fenótipo Proteólise Interferência de RNA Espécies Reativas de Oxigênio/metabolismo Receptores do Fator Autócrino de Motilidade/genética Receptores do Fator Autócrino de Motilidade/metabolismo Esterol O-Aciltransferase/deficiência Esterol O-Aciltransferase/genética Fatores de Tempo Transfecção Ubiquitinação [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Cholesterol Esters); 0 (Fatty Acids); 0 (Reactive Oxygen Species); 97C5T2UQ7J (Cholesterol); EC 2.3.1.26 (Sterol O-Acyltransferase); EC 2.3.1.26 (sterol O-acyltransferase 2); EC 2.3.2.27 (Amfr protein, mouse); EC 2.3.2.27 (Receptors, Autocrine Motility Factor); K848JZ4886 (Cysteine) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170913 [Lr] Data última revisão: 170913 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170613 [St] Status: MEDLINE [do] DOI: 10.1038/ncb3551

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[PMID]: 28595267 [Au] Autor: Stopsack KH; Gerke TA; Andrén O; Andersson SO; Giovannucci EL; Mucci LA; Rider JR [Ad] Endereço: To whom correspondence should be addressed. Tel: +507 284 2511; Fax: +507 266 1799; Email: stopsack@post.harvard.edu [Ti] Título: Cholesterol uptake and regulation in high-grade and lethal prostate cancers. [So] Source: Carcinogenesis;38(8):806-811, 2017 08 01. [Is] ISSN: 1460-2180 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Lethal prostate cancers have higher expression of squalene monooxygenase (SQLE), the second rate-limiting enzyme of cholesterol synthesis. Preclinical studies suggested that aberrant cholesterol regulators, receptors and transporters contribute to cholesterol accumulation uniformly. We assessed their association with features of aggressive cancers. In the prospective prostate cancer cohorts within the Health Professional Follow-up Study, the Physicians' Health Study and the Swedish Watchful Waiting Study, tumor mRNA expression profiling was performed. Lethal disease was defined as mortality or metastases from prostate cancer (n = 266) in contrast to non-lethal disease without metastases after >8 years of follow-up (n = 476). Associations with Gleason grade were additionally assessed using The Cancer Genome Atlas primary prostate cancer dataset (n = 333). Higher Gleason grade was associated with lower LDLR expression, lower SOAT1 and higher SQLE expression. Besides high SQLE expression, cancers that became lethal despite primary treatment were characterized by low LDLR expression (odds ratio for highest versus lowest quintile, 0.37; 95% CI 0.18-0.76) and by low SOAT1 expression (odds ratio, 0.41; 95% CI 0.21-0.83). The association of LDLR expression and lethality was not present in tumors with high IDOL expression. ABCA1, PCSK9 or SCARB1 expressions were not associated with Gleason grade or lethal cancer. In summary, prostate cancers that progress to lethal disease rely on de novo cholesterol synthesis (via SQLE), rather than transcellular uptake (via LDLR) or cholesterol esterification (via SOAT1). These results may help design pharmacotherapy for high-risk patients. [Mh] Termos MeSH primário: Colesterol/metabolismo NADH NADPH Oxirredutases/genética Neoplasias da Próstata/metabolismo Receptores de LDL/genética Esterol O-Aciltransferase/genética [Mh] Termos MeSH secundário: Regulação Neoplásica da Expressão Gênica Seres Humanos Masculino Gradação de Tumores Neoplasias da Próstata/genética Neoplasias da Próstata/patologia Esqualeno Mono-Oxigenase/genética Esqualeno Mono-Oxigenase/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (LDLR protein, human); 0 (Receptors, LDL); 97C5T2UQ7J (Cholesterol); EC 1.14.14.17 (Squalene Monooxygenase); EC 1.6.- (NADH, NADPH Oxidoreductases); EC 1.6.5.3 (NDUFB7 protein, human); EC 2.3.1.26 (Sterol O-Acyltransferase); EC 2.3.1.26 (sterol O-acyltransferase 1) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171005 [Lr] Data última revisão: 171005 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170609 [St] Status: MEDLINE [do] DOI: 10.1093/carcin/bgx058

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[PMID]: 28294609 [Au] Autor: Iwasaki A; Tadenuma T; Sumimoto S; Ohshiro T; Ozaki K; Kobayashi K; Teruya T; Tomoda H; Suenaga K [Ad] Endereço: Department of Chemistry, Faculty of Science and Technology, Keio University , 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan. [Ti] Título: Biseokeaniamides A, B, and C, Sterol O-Acyltransferase Inhibitors from an Okeania sp. Marine Cyanobacterium. [So] Source: J Nat Prod;80(4):1161-1166, 2017 Apr 28. [Is] ISSN: 1520-6025 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Biseokeaniamides A, B, and C (1-3), structurally novel sterol O-acyltransferase (SOAT) inhibitors, were isolated from an Okeania sp. marine cyanobacterium. Their structures were elucidated by spectroscopic analyses and degradation reactions. Biseokeaniamide B (2) exhibited moderate cytotoxicity against human HeLa cancer cells, and compounds 1-3 inhibited both SOAT1 and SOAT2, not only at an enzyme level but also at a cellular level. Biseokeaniamides (1-3) are the first linear lipopeptides that have been shown to exhibit SOAT-inhibitory activity. [Mh] Termos MeSH primário: Antineoplásicos/isolamento & purificação Antineoplásicos/farmacologia Cianobactérias/química Lipopeptídeos/isolamento & purificação Lipopeptídeos/farmacologia Esterol O-Aciltransferase/antagonistas & inibidores [Mh] Termos MeSH secundário: Antineoplásicos/química Caspase 3/metabolismo Células HeLa Seres Humanos Lipopeptídeos/química Biologia Marinha Estrutura Molecular Ressonância Magnética Nuclear Biomolecular [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Lipopeptides); 0 (biseokeaniamide A); 0 (biseokeaniamide B); 0 (biseokeaniamide C); EC 2.3.1.26 (Sterol O-Acyltransferase); EC 3.4.22.- (Caspase 3) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 170726 [Lr] Data última revisão: 170726 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170316 [St] Status: MEDLINE [do] DOI: 10.1021/acs.jnatprod.7b00137

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[PMID]: 28242547 [Au] Autor: Pal P; Gandhi HP; Kanhed AM; Patel NR; Mankadia NN; Baldha SN; Barmade MA; Murumkar PR; Yadav MR [Ad] Endereço: Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara, 390001, India. [Ti] Título: Vicinal diaryl azole-based urea derivatives as potential cholesterol lowering agents acting through inhibition of SOAT enzymes. [So] Source: Eur J Med Chem;130:107-123, 2017 Apr 21. [Is] ISSN: 1768-3254 [Cp] País de publicação: France [La] Idioma: eng [Ab] Resumo: A novel series of vicinal diaryl azole-urea derivatives were synthesized and evaluated for their potential to inhibit SOAT enzyme. Among the reported compounds, compound (12d) emerged as the most potent compound with an IC value of 2.43 µM. In polaxamer-407 induced lipoprotein lipase inhibition model, compound (12d) reduced triglyceride turnover in vivo. Compound (12d) also showed dose-dependent prevention of serum total cholesterol and prevention of LDL-C elevation at a dose of 30 mg/kg. Furthermore, compound (12d) showed potential to stop falling levels of serum HDL-C dose-dependently and improved the atherogenic index. Effect of 12d on body weight, plaque formation and development of atherogenic lesions were studied. Toxicological study of compound (12d) indicated that at a dose of 2000 mg/kg, 12d was devoid of any signs of toxicity or mortality. [Mh] Termos MeSH primário: Anticolesterolemiantes/química Azóis/farmacologia Inibidores Enzimáticos/química Esterol O-Aciltransferase/antagonistas & inibidores Ureia/farmacologia [Mh] Termos MeSH secundário: Animais Anticolesterolemiantes/farmacologia Aterosclerose/prevenção & controle Azóis/química Colesterol/sangue LDL-Colesterol/sangue LDL-Colesterol/efeitos dos fármacos Inibidores Enzimáticos/farmacologia Seres Humanos Hipolipemiantes/farmacologia Lipase Lipoproteica/antagonistas & inibidores Triglicerídeos/sangue Ureia/química [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Anticholesteremic Agents); 0 (Azoles); 0 (Cholesterol, LDL); 0 (Enzyme Inhibitors); 0 (Hypolipidemic Agents); 0 (Triglycerides); 8W8T17847W (Urea); 97C5T2UQ7J (Cholesterol); EC 2.3.1.26 (Sterol O-Acyltransferase); EC 3.1.1.34 (Lipoprotein Lipase) [Em] Mês de entrada: 1703 [Cu] Atualização por classe: 170322 [Lr] Data última revisão: 170322 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170301 [St] Status: MEDLINE

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[PMID]: 27392637 [Au] Autor: Geyer J; Bakhaus K; Bernhardt R; Blaschka C; Dezhkam Y; Fietz D; Grosser G; Hartmann K; Hartmann MF; Neunzig J; Papadopoulos D; Sánchez-Guijo A; Scheiner-Bobis G; Schuler G; Shihan M; Wrenzycki C; Wudy SA; Bergmann M [Ad] Endereço: Institute of Pharmacology and Toxicology, Justus Liebig University, Giessen, Germany. Electronic address: Joachim.M.Geyer@vetmed.uni-giessen.de. [Ti] Título: The role of sulfated steroid hormones in reproductive processes. [So] Source: J Steroid Biochem Mol Biol;172:207-221, 2017 Sep. [Is] ISSN: 1879-1220 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Sulfated steroid hormones, such as dehydroepiandrosterone sulfate or estrone-3-sulfate, have long been regarded as inactive metabolites as they cannot activate classical steroid receptors. Some of them are present in the blood circulation at quite high concentrations, but generally sulfated steroids exhibit low membrane permeation due to their hydrophilic properties. However, sulfated steroid hormones can actively be imported into specific target cells via uptake carriers, such as the sodium-dependent organic anion transporter SOAT, and, after hydrolysis by the steroid sulfatase (so-called sulfatase pathway), contribute to the overall regulation of steroid responsive organs. To investigate the biological significance of sulfated steroid hormones for reproductive processes in humans and animals, the research group "Sulfated Steroids in Reproduction" was established by the German Research Foundation DFG (FOR1369). Projects of this group deal with transport of sulfated steroids, sulfation of free steroids, desulfation by the steroid sulfatase, effects of sulfated steroids on steroid biosynthesis and membrane receptors as well as MS-based profiling of sulfated steroids in biological samples. This review and concept paper presents key findings from all these projects and provides a broad overview over the current research on sulfated steroid hormones in the field of reproduction. [Mh] Termos MeSH primário: Sulfato de Desidroepiandrosterona/metabolismo Estrona/análogos & derivados Ictiose Ligada ao Cromossomo X/metabolismo Reprodução/genética Esterol O-Aciltransferase/metabolismo Esteril-Sulfatase/metabolismo [Mh] Termos MeSH secundário: Animais Transporte Biológico Bovinos Estrona/metabolismo Feminino Expressão Gênica Seres Humanos Hidroxicolesteróis/metabolismo Ictiose Ligada ao Cromossomo X/genética Ictiose Ligada ao Cromossomo X/patologia Masculino Oócitos/citologia Oócitos/metabolismo Placenta/citologia Placenta/metabolismo Gravidez Esterol O-Aciltransferase/genética Esteril-Sulfatase/genética Suínos [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Hydroxycholesterols); 2DI9HA706A (Estrone); 57B09Q7FJR (Dehydroepiandrosterone Sulfate); EC 2.3.1.26 (Sterol O-Acyltransferase); EC 2.3.1.26 (sterol O-acyltransferase 1); EC 3.1.6.2 (Steryl-Sulfatase); QTL48N278K (estrone sulfate) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170822 [Lr] Data última revisão: 170822 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160710 [St] Status: MEDLINE

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[PMID]: 27936201 [Au] Autor: Chang NY; Chan YJ; Ding ST; Lee YH; HuangFu WC; Liu IH [Ad] Endereço: Department of Animal Science and Technology, National Taiwan University, Taipei, Taiwan. [Ti] Título: Sterol O-Acyltransferase 2 Contributes to the Yolk Cholesterol Trafficking during Zebrafish Embryogenesis. [So] Source: PLoS One;11(12):e0167644, 2016. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: To elucidate whether Sterol O-acyltransferase (Soat) mediates the absorption and transportation of yolk lipids to the developing embryo, zebrafish soat1 and soat2 were cloned and studied. In the adult zebrafish, soat1 was detected ubiquitously while soat2 mRNA was detected specifically in the liver, intestine, brain and testis. Whole mount in situ hybridization demonstrated that both soat1 and soat2 expressed in the yolk syncytial layer, hatching gland and developing cardiovascular as well as digestive systems, suggesting that Soats may play important roles in the lipid trafficking and utilization during embryonic development. The enzymatic activity of zebrafish Soat2 was confirmed by Oil Red O staining in the HEK293 cells overexpressing this gene, and could be quenched by Soat2 inhibitor Pyripyropene A (PPPA). The zebrafish embryos injected with PPPA or morpholino oligo against soat2 in the yolk showed significantly larger yolk when compared with wild-type embryos, especially at 72 hpf, indicating a slower rate of yolk consumption. Our result indicated that zebrafish Soat2 is catalytically active in synthesizing cholesteryl esters and contributes to the yolk cholesterol trafficking during zebrafish embryogenesis. [Mh] Termos MeSH primário: Colesterol/metabolismo Gema de Ovo/metabolismo Esterol O-Aciltransferase/metabolismo Proteínas de Peixe-Zebra/metabolismo Peixe-Zebra/embriologia [Mh] Termos MeSH secundário: Sequência de Aminoácidos Animais Ésteres do Colesterol/metabolismo Células HEK293 Seres Humanos Alinhamento de Sequência Esterol O-Aciltransferase/análise Peixe-Zebra/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Cholesterol Esters); 0 (Zebrafish Proteins); 97C5T2UQ7J (Cholesterol); EC 2.3.1.26 (Sterol O-Acyltransferase); EC 2.3.1.26 (sterol O-acyltransferase 2) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 170706 [Lr] Data última revisão: 170706 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161210 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0167644

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[PMID]: 27688151 [Au] Autor: Guo D; Lu M; Hu X; Xu J; Hu G; Zhu M; Zhang X; Li Q; Chang CC; Chang T; Song B; Xiong Y; Li B [Ad] Endereço: Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. [Ti] Título: Low-level expression of human ACAT2 gene in monocytic cells is regulated by the C/EBP transcription factors. [So] Source: Acta Biochim Biophys Sin (Shanghai);48(11):980-989, 2016 Nov. [Is] ISSN: 1745-7270 [Cp] País de publicação: China [La] Idioma: eng [Ab] Resumo: Acyl-coenzyme A:cholesterol acyltransferases (ACATs) are the exclusive intracellular enzymes that catalyze the formation of cholesteryl/steryl esters (CE/SE). In our previous work, we found that the high-level expression of human ACAT2 gene with the CpG hypomethylation of its whole promoter was synergistically regulated by two transcription factors Cdx2 and HNF1α in the intestine and fetal liver. Here, we first observed that the specific CpG-hypomethylated promoter was correlated with the low expression of human ACAT2 gene in monocytic cell line THP-1. Then, two CCAAT/enhancer binding protein (C/EBP) elements within the activation domain in the specific CpG-hypomethylation promoter region were identified, and the expression of ACAT2 in THP-1 cells was evidently decreased when the C/EBP transcription factors were knock-downed using RNAi technology. Furthermore, ChIP assay confirmed that C/EBPs directly bind to their elements for low-level expression of human ACAT2 gene in THP-1 cells. Significantly, the increased expressions of ACAT2 and C/EBPs were also found in macrophages differentiated from both ATRA-treated THP-1 cells and cultured human blood monocytes. These results demonstrate that the low-level expression of human ACAT2 gene with specific CpG-hypomethylated promoter is regulated by the C/EBP transcription factors in monocytic cells, and imply that the lowly expressed ACAT2 catalyzes the synthesis of certain CE/SE that are assembled into lipoproteins for the secretion. [Mh] Termos MeSH primário: Proteínas Estimuladoras de Ligação a CCAAT/fisiologia Regulação da Expressão Gênica/fisiologia Monócitos/metabolismo Esterol O-Aciltransferase/genética [Mh] Termos MeSH secundário: Proteínas Estimuladoras de Ligação a CCAAT/metabolismo Diferenciação Celular Linhagem Celular Ilhas de CpG Metilação de DNA Seres Humanos Macrófagos/citologia Regiões Promotoras Genéticas Ligação Proteica [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (CCAAT-Enhancer-Binding Proteins); EC 2.3.1.26 (Sterol O-Acyltransferase); EC 2.3.1.26 (sterol O-acyltransferase 2) [Em] Mês de entrada: 1702 [Cu] Atualização por classe: 171101 [Lr] Data última revisão: 171101 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161001 [St] Status: MEDLINE

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[PMID]: 27688150 [Au] Autor: Guo D; Zhang X; Li Q; Qian L; Xu J; Lu M; Hu X; Zhu M; Chang CC; Song B; Chang T; Xiong Y; Li B [Ad] Endereço: Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. [Ti] Título: The ACAT2 expression of human leukocytes is responsible for the excretion of lipoproteins containing cholesteryl/steryl esters. [So] Source: Acta Biochim Biophys Sin (Shanghai);48(11):990-997, 2016 Nov. [Is] ISSN: 1745-7270 [Cp] País de publicação: China [La] Idioma: eng [Ab] Resumo: Acyl-coenzymeA:cholesterol acyltransferase 2 (ACAT2) is abundantly expressed in intestine and fetal liver of healthy human. Our previous studies have shown that in monocytic cells the low-level expression of human ACAT2 gene with specific CpG-hypomethylated promoter is regulated by the CCAAT/enhancer binding protein (C/EBP) transcription factors. In this study, we further report that the ACAT2 gene expression is attributable to the C/EBPs in the human leukocytes and correlated with the excretion of fluorescent lipoproteins containing the ACAT2-catalyzed NBD22-steryl esters. Moreover, this lipoprotein excretion can be inhibited by the ACAT2 isoform-selective inhibitor pyripyropene A (PPPA) in a dose-dependent manner, and employed to determine the half maximum inhibitory concentration (IC ) values of PPPA. Significantly, it is found that the differentiation-inducing factor all-trans retinoic acid, but not the proinflammatory cytokine tumor necrosis factor-α, enhances this ACAT2-dependent lipoprotein excretion. These data demonstrate that the ACAT2 expression of human leukocytes is responsible for the excretion of lipoproteins containing cholesteryl/steryl esters (CE/SE), and suggest that the excretion of lipoproteins containing the ACAT2-catalyzed CS/SE may avoid cytotoxicity through decreasing the excess intracellular cholesterols/sterols (especially various oxysterols), which is essential for the action of the human leukocytes. [Mh] Termos MeSH primário: Ésteres do Colesterol/metabolismo Leucócitos/enzimologia Lipoproteínas/metabolismo Esterol O-Aciltransferase/genética [Mh] Termos MeSH secundário: Linhagem Celular Expressão Gênica Seres Humanos Leucócitos/efeitos dos fármacos Tretinoína/farmacologia Fator de Necrose Tumoral alfa/farmacologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Cholesterol Esters); 0 (Lipoproteins); 0 (Tumor Necrosis Factor-alpha); 5688UTC01R (Tretinoin); EC 2.3.1.26 (Sterol O-Acyltransferase); EC 2.3.1.26 (sterol O-acyltransferase 2) [Em] Mês de entrada: 1702 [Cu] Atualização por classe: 171101 [Lr] Data última revisão: 171101 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161001 [St] Status: MEDLINE

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[PMID]: 27482889 [Au] Autor: Pedigo CE; Ducasa GM; Leclercq F; Sloan A; Mitrofanova A; Hashmi T; Molina-David J; Ge M; Lassenius MI; Forsblom C; Lehto M; Groop PH; Kretzler M; Eddy S; Martini S; Reich H; Wahl P; Ghiggeri G; Faul C; Burke GW; Kretz O; Huber TB; Mendez AJ; Merscher S; Fornoni A [Ti] Título: Local TNF causes NFATc1-dependent cholesterol-mediated podocyte injury. [So] Source: J Clin Invest;126(9):3336-50, 2016 Sep 01. [Is] ISSN: 1558-8238 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: High levels of circulating TNF and its receptors, TNFR1 and TNFR2, predict the progression of diabetic kidney disease (DKD), but their contribution to organ damage in DKD remains largely unknown. Here, we investigated the function of local and systemic TNF in podocyte injury. We cultured human podocytes with sera collected from DKD patients, who displayed elevated TNF levels, and focal segmental glomerulosclerosis (FSGS) patients, whose TNF levels resembled those of healthy patients. Exogenous TNF administration or local TNF expression was equally sufficient to cause free cholesterol-dependent apoptosis in podocytes by acting through a dual mechanism that required a reduction in ATP-binding cassette transporter A1-mediated (ABCA1-mediated) cholesterol efflux and reduced cholesterol esterification by sterol-O-acyltransferase 1 (SOAT1). TNF-induced albuminuria was aggravated in mice with podocyte-specific ABCA1 deficiency and was partially prevented by cholesterol depletion with cyclodextrin. TNF-stimulated free cholesterol-dependent apoptosis in podocytes was mediated by nuclear factor of activated T cells 1 (NFATc1). ABCA1 overexpression or cholesterol depletion was sufficient to reduce albuminuria in mice with podocyte-specific NFATc1 activation. Our data implicate an NFATc1/ABCA1-dependent mechanism in which local TNF is sufficient to cause free cholesterol-dependent podocyte injury irrespective of TNF, TNFR1, or TNFR2 serum levels. [Mh] Termos MeSH primário: Colesterol/química Nefropatias Diabéticas/sangue Glomerulosclerose Segmentar e Focal/sangue Fatores de Transcrição NFATC/fisiologia Síndrome Nefrótica/sangue Fator de Necrose Tumoral alfa/fisiologia [Mh] Termos MeSH secundário: Transportador 1 de Cassete de Ligação de ATP/fisiologia Adolescente Albuminúria/sangue Animais Apoptose Biópsia Estudos de Casos e Controles Criança Pré-Escolar Ciclodextrinas/metabolismo Feminino Regulação da Expressão Gênica Taxa de Filtração Glomerular Seres Humanos Inflamação Rim/metabolismo Masculino Camundongos Camundongos Endogâmicos BALB C Podócitos/metabolismo Receptores Tipo I de Fatores de Necrose Tumoral/sangue Receptores Tipo II do Fator de Necrose Tumoral/sangue Esterol O-Aciltransferase/fisiologia Fator de Necrose Tumoral alfa/farmacologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (ABCA1 protein, human); 0 (ABCA1 protein, mouse); 0 (ATP Binding Cassette Transporter 1); 0 (Cyclodextrins); 0 (NFATC Transcription Factors); 0 (NFATC1 protein, human); 0 (Nfatc1 protein, mouse); 0 (Receptors, Tumor Necrosis Factor, Type I); 0 (Receptors, Tumor Necrosis Factor, Type II); 0 (TNFRSF1A protein, human); 0 (TNFRSF1B protein, human); 0 (Tumor Necrosis Factor-alpha); 97C5T2UQ7J (Cholesterol); EC 2.3.1.26 (Sterol O-Acyltransferase); EC 2.3.1.26 (sterol O-acyltransferase 1) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170926 [Lr] Data última revisão: 170926 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 160803 [St] Status: MEDLINE

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