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[PMID]: 29260551 [Au] Autor: Zhang L; Zhang H; Song Y [Ad] Endereço: Colin Ratledge Center for Microbial Lipids, School of Agricultural Engineering and Food Science, Shandong University of Technology , Zibo, 255049 Shandong, People's Republic of China. [Ti] Título: Identification and Characterization of Diacylglycerol Acyltransferase from Oleaginous Fungus Mucor circinelloides. [So] Source: J Agric Food Chem;66(3):674-681, 2018 Jan 24. [Is] ISSN: 1520-5118 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Acyl-CoA:diacylglycerol acyltransferase (DGAT) is a pivotal regulator of triacylglycerol (TAG) synthesis. The oleaginous fungus Mucor circinelloides has four putative DGATs: McDGAT1A, McDGAT1B, McDGAT2A, and McDGAT2B, classified into the DGAT1 and DGAT2 subfamilies, respectively. To identify and characterize DGATs in M. circinelloides, these four genes were expressed in Saccharomyces cerevisiae H1246 (TAG-deficient quadruple mutant), individually. TAG biosynthesis was restored only by the expression of McDGAT2B, and TAG content was significantly higher in the mutants with McDGAT2B expression than in a S. cerevisiae mutant with endogenous DGA1 expression. McDGAT2B prefers saturated fatty acids to monounsaturated fatty acids and has an obvious preference for C18:3 (ω-6) according to the results of substrate preference experiments. Furthermore, only the mRNA expression pattern of McDGAT2B correlated with TAG biosynthesis during a fermentation process. Our experiments strongly indicate that McDGAT2B is crucial for TAG accumulation, suggesting that it may be an essential target for metabolic engineering aimed at increasing lipid content of M. circinelloides. [Mh] Termos MeSH primário: Diacilglicerol O-Aciltransferase/química Proteínas Fúngicas/química Mucor/enzimologia [Mh] Termos MeSH secundário: Sequência de Aminoácidos Diacilglicerol O-Aciltransferase/genética Diacilglicerol O-Aciltransferase/metabolismo Ácidos Graxos/química Ácidos Graxos/metabolismo Proteínas Fúngicas/genética Proteínas Fúngicas/metabolismo Dados de Sequência Molecular Mucor/química Mucor/genética Família Multigênica Alinhamento de Sequência Especificidade por Substrato [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Fatty Acids); 0 (Fungal Proteins); EC 2.3.1.20 (Diacylglycerol O-Acyltransferase) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180207 [Lr] Data última revisão: 180207 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171221 [St] Status: MEDLINE [do] DOI: 10.1021/acs.jafc.7b04295

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[PMID]: 29198193 [Au] Autor: Cai Z; Mai K; Ai Q [Ad] Endereço: Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture) & Key Laboratory of Mariculture (Ministry of Education),Ocean University of China,5 Yushan Road,Qingdao,Shandong 266003,People's Republic of China. [Ti] Título: Regulation of hepatic lipid deposition by phospholipid in large yellow croaker. [So] Source: Br J Nutr;118(12):999-1009, 2017 Dec. [Is] ISSN: 1475-2662 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Dietary phospholipid (PL) supplementation has been shown to reduce lipid accumulation in the tissues of farmed fish; however, the mechanisms underlying this effect are largely unknown. Thus, the present study was conducted to evaluate the potential impacts of PL on hepatic lipid metabolism both in vivo and in vitro. For in vivo study, four experimental diets - low lipid and low PL diet, as control diet (LL-LP diet, containing 12 % lipid and 1·5 % PL), low-lipid and high-PL diet (containing 12 % lipid and 8 % PL), high-lipid and low-PL diet (HL-LP diet, containing 20 % lipid and 1·5 % PL) and high-lipid and high-PL diet (HL-HP diet, containing 20 % lipid and 8 % PL) - were randomly allocated to four groups of large yellow croaker (Larimichthys crocea) (three cages per group) with similar initial body weight (approximately 8 g). For in vitro study, primary hepatocytes isolated from large yellow croaker were incubated either with graded levels of phosphatidylcholine (PC) (0-250 µm) or small interfering RNA (siRNA) for CTP: choline phosphate cytidylyltranferase α (CCTα) (siRNA-CCTα). Results showed that survival was independent of dietary treatments (P>0·05). Weight gain and feed efficiency in the HL-HP group were significantly higher than in the LL-LP and HL-LP groups (P<0·05). High level of dietary PL could markedly reduce abnormal hepatic lipid accumulation induced by the HL-LP diet (P<0·05). Similarly, compared with the corresponding controls, a significant decrease/increase in lipid content was observed in primary hepatocytes incubated with PC/siRNA-CCTα (P<0·05). High level of dietary PL reversed the HL-LP diet-induced increased levels of mRNA of fatty acid uptake and lipid synthesis related genes (P<0·05). In addition, High level of dietary PL markedly down-regulated the transcript levels of fatty acid oxidation-related genes and enhanced the transcript levels of VLDL assembly-related genes regardless of dietary lipid levels (P<0·05). Compared with corresponding controls, primary hepatocytes treated with PC showed significantly higher mRNA expression of lipid synthesis and VLDL assembly-related genes and lower mRNA expression of fatty acid oxidation-related genes, with hepatocytes treated with siRNA-CCTα exhibiting the opposite trend (P<0·05). In summary, these results demonstrated that high level of dietary PL might reverse the HL-LP diet-induced abnormal lipid accumulation in the liver through inhibiting fatty acid uptake and lipid synthesis, together with promoting the lipid export at the transcriptional level. Lipid export-promoting effect of PC was confirmed by in vitro studies. The present study showed for the first time that PL or PC could influence various metabolic pathways to regulate hepatic lipid deposition in fish at least at the transcriptional level. [Mh] Termos MeSH primário: Dieta/veterinária Metabolismo dos Lipídeos Fígado/metabolismo Perciformes/metabolismo Fosfolipídeos/administração & dosagem [Mh] Termos MeSH secundário: Ração Animal Animais Antígenos CD36/genética Antígenos CD36/metabolismo Células Cultivadas Diacilglicerol O-Aciltransferase/genética Diacilglicerol O-Aciltransferase/metabolismo Ácido Graxo Sintases/genética Ácido Graxo Sintases/metabolismo Proteínas de Transporte de Ácido Graxo/genética Proteínas de Transporte de Ácido Graxo/metabolismo Proteínas de Ligação a Ácido Graxo/genética Proteínas de Ligação a Ácido Graxo/metabolismo Ácidos Graxos/metabolismo Proteínas de Peixes/genética Proteínas de Peixes/metabolismo Hepatócitos/metabolismo Lipase/genética Lipase/metabolismo Lipase Lipoproteica/genética Lipase Lipoproteica/metabolismo Fosfatidilcolinas/administração & dosagem Proteína de Ligação a Elemento Regulador de Esterol 1/genética Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (CD36 Antigens); 0 (Fatty Acid Transport Proteins); 0 (Fatty Acid-Binding Proteins); 0 (Fatty Acids); 0 (Fish Proteins); 0 (Phosphatidylcholines); 0 (Phospholipids); 0 (Sterol Regulatory Element Binding Protein 1); EC 2.3.1.20 (Diacylglycerol O-Acyltransferase); EC 2.3.1.85 (Fatty Acid Synthases); EC 3.1.1.3 (Lipase); EC 3.1.1.34 (Lipoprotein Lipase) [Em] Mês de entrada: 1712 [Cu] Atualização por classe: 171227 [Lr] Data última revisão: 171227 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171205 [St] Status: MEDLINE [do] DOI: 10.1017/S000711451700294X

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[PMID]: 28900030 [Au] Autor: Xu Y; Chen G; Greer MS; Caldo KMP; Ramakrishnan G; Shah S; Wu L; Lemieux MJ; Ozga J; Weselake RJ [Ad] Endereço: From the Department of Agricultural, Food, and Nutritional Science, University of Alberta, Edmonton, Alberta T6G 2P5. [Ti] Título: Multiple mechanisms contribute to increased neutral lipid accumulation in yeast producing recombinant variants of plant diacylglycerol acyltransferase 1. [So] Source: J Biol Chem;292(43):17819-17831, 2017 Oct 27. [Is] ISSN: 1083-351X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The apparent bottleneck in the accumulation of oil during seed development in some oleaginous plant species is the formation of triacylglycerol (TAG) by the acyl-CoA-dependent acylation of -1,2-diacylglycerol catalyzed by diacylglycerol acyltransferase (DGAT, EC 2.3.1.20). Improving DGAT activity using protein engineering could lead to improvements in seed oil yield ( in canola-type ). Directed evolution of DGAT1 (BnaDGAT1) previously revealed that one of the regions where amino acid residue substitutions lead to higher performance in BnaDGAT1 is in the ninth predicted transmembrane domain (PTMD9). In this study, several BnaDGAT1 variants with amino acid residue substitutions in PTMD9 were characterized. Among these enzyme variants, the extent of yeast TAG production was affected by different mechanisms, including increased enzyme activity, increased polypeptide accumulation, and possibly reduced substrate inhibition. The kinetic properties of the BnaDGAT1 variants were affected by the amino acid residue substitutions, and a new kinetic model based on substrate inhibition and sigmoidicity was generated. Based on sequence alignment and further biochemical analysis, the amino acid residue substitutions that conferred increased TAG accumulation were shown to be present in the DGAT1-PTMD9 region of other higher plant species. When amino acid residue substitutions that increased BnaDGAT1 enzyme activity were introduced into recombinant DGAT1, they also improved enzyme performance. Thus, the knowledge generated from directed evolution of DGAT1 in one plant species can be transferred to other plant species and has potentially broad applications in genetic engineering of oleaginous crops and microorganisms. [Mh] Termos MeSH primário: Brassica napus/genética Diacilglicerol O-Aciltransferase Metabolismo dos Lipídeos Proteínas de Plantas Saccharomyces cerevisiae/enzimologia [Mh] Termos MeSH secundário: Substituição de Aminoácidos Brassica napus/enzimologia Diacilglicerol O-Aciltransferase/biossíntese Diacilglicerol O-Aciltransferase/genética Mutação de Sentido Incorreto Organismos Geneticamente Modificados/genética Organismos Geneticamente Modificados/metabolismo Proteínas de Plantas/biossíntese Proteínas de Plantas/genética Proteínas Recombinantes/biossíntese Proteínas Recombinantes/genética Saccharomyces cerevisiae/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Plant Proteins); 0 (Recombinant Proteins); EC 2.3.1.20 (Diacylglycerol O-Acyltransferase) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171103 [Lr] Data última revisão: 171103 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170914 [St] Status: MEDLINE [do] DOI: 10.1074/jbc.M117.811489

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[PMID]: 28796890 [Au] Autor: Uyama T; Tsuboi K; Ueda N [Ad] Endereço: Department of Biochemistry, Kagawa University School of Medicine, Japan. [Ti] Título: An involvement of phospholipase A/acyltransferase family proteins in peroxisome regulation and plasmalogen metabolism. [So] Source: FEBS Lett;591(18):2745-2760, 2017 Sep. [Is] ISSN: 1873-3468 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: The H-Ras-like suppressor (HRASLS) is a protein family consisting of five members in humans. Despite their discovery as tumor suppressors, we demonstrated that all these proteins are phospholipid-metabolizing enzymes, such as phospholipase (PL) A /A and acyltransferase. We thus proposed to rename HRASLS1-5 as PLA/acyltransferase (PLAAT)-1-5. Notably, PLAATs exhibit N-acyltransferase activity to biosynthesize N-acylated ethanolamine phospholipids, including N-acyl-plasmalogen, which serve as precursors of bioactive N-acylethanolamines. Furthermore, the overexpression of PLAAT-3 in animal cells causes disappearance of peroxisomes and a remarkable reduction in plasmalogen levels. This finding might be related to the inhibitory effect of PLAAT-3 on the chaperone activity of the peroxin PEX19. In this article, we will review our recent findings about PLAAT proteins, with special reference to their roles in peroxisome biogenesis and plasmalogen metabolism. [Mh] Termos MeSH primário: Peroxissomos/metabolismo Plasmalogênios/metabolismo [Mh] Termos MeSH secundário: Animais Diacilglicerol O-Aciltransferase/metabolismo Etanolaminas/metabolismo Seres Humanos Proteínas de Membrana/metabolismo Fosfolipases A1/metabolismo Fosfolipases A2/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Ethanolamines); 0 (Membrane Proteins); 0 (N-acylethanolamines); 0 (Plasmalogens); EC 2.3.1.20 (Diacylglycerol O-Acyltransferase); EC 3.1.1.32 (Phospholipases A1); EC 3.1.1.4 (Phospholipases A2) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171011 [Lr] Data última revisão: 171011 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170811 [St] Status: MEDLINE [do] DOI: 10.1002/1873-3468.12787

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[PMID]: 28763157 [Au] Autor: Wallstab C; Eleftheriadou D; Schulz T; Damm G; Seehofer D; Borlak J; Holzhütter HG; Berndt N [Ad] Endereço: Institute of Biochemistry, Computational Systems Biochemistry Group, Charite - University Medicine Berlin, Germany. [Ti] Título: A unifying mathematical model of lipid droplet metabolism reveals key molecular players in the development of hepatic steatosis. [So] Source: FEBS J;284(19):3245-3261, 2017 Oct. [Is] ISSN: 1742-4658 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: The liver responds to elevated plasma concentrations of free fatty acids (FFAs) with an enhanced uptake of FFAs and their esterification to triacylglycerol (TAG). On the long term, this may result in massive hepatic TAG accumulation called steatosis hepatitis. In hepatocytes, the poor water-soluble TAG is packed in specialized organelles: Lipid droplets (LDs) serving as transient cellular deposit and lipoproteins (LPs) transporting TAG and cholesterol esters to extra-hepatic tissues. The dynamics of these organelles is controlled by a variety of regulatory surface proteins (RSPs). Assembly and export of VLDLs are mainly regulated by the microsomal transfer protein (MTP) and apoprotein B100. Formation and lipolysis of LDs are regulated by several RSPs. The best studied regulators belong to the PAT (Perilipin/Adipophilin/TIP47) and CIDE families. Knockdown or overexpression of SRPs may significantly affect the total number and size distribution of LDs. Intriguingly, a large cell-to-cell heterogeneity with respect to the number and size of LDs has been found in various cell types including hepatocytes. These findings suggest that the extent of cellular lipid accumulation is determined not only by the imbalance between lipid supply and utilization but also by variations in the expression of RSPs and metabolic enzymes. To better understand the relative regulatory impact of individual processes involved in the cellular TAG turnover, we developed a comprehensive kinetic model encompassing the pathways of the fatty acid and triglyceride metabolism and the main molecular processes governing the dynamics of LDs. The model was parametrized such that a large number of experimental in vitro and in vivo findings are correctly recapitulated. A control analysis of the model revealed that variations in the activity of FFA uptake, diacylglycerol acyltransferase (DGAT) 2, and adipose triglyceride lipase (ATGL) have the strongest influence on the cellular TAG level. We used the model to simulate LD size distributions in human hepatoma cells and hepatocytes exposed to a challenge with FFAs. A random fold change by a factor of about two in the activity of RSPs was sufficient to reproduce the large diversity of droplet size distributions observed in individual cells. Under the premise that the same extent of variability of RSPs holds for the intact organ, our model predicts variations in the TAG content of individual hepatocytes by a factor of about 3-6 depending on the nutritional regime. Taken together, our modeling approach integrates numerous experimental findings on individual processes in the cellular TAG metabolism and LD dynamics metabolism to a consistent state-of-the-art dynamic network model that can be used to study how changes in the external conditions or systemic parameters will affect the TAG content of hepatocytes. [Mh] Termos MeSH primário: Fígado Gorduroso/metabolismo Hepatócitos/metabolismo Gotículas Lipídicas/metabolismo Metabolismo dos Lipídeos/genética Modelos Estatísticos [Mh] Termos MeSH secundário: Linhagem Celular Tumoral Ésteres do Colesterol/metabolismo Diacilglicerol O-Aciltransferase/genética Diacilglicerol O-Aciltransferase/metabolismo Fígado Gorduroso/induzido quimicamente Fígado Gorduroso/genética Fígado Gorduroso/patologia Regulação da Expressão Gênica Hepatócitos/citologia Hepatócitos/efeitos dos fármacos Seres Humanos Lipase/genética Lipase/metabolismo Gotículas Lipídicas/química Metabolismo dos Lipídeos/efeitos dos fármacos Modelos Biológicos Ácido Oleico/metabolismo Ácido Oleico/farmacologia Ácido Palmítico/metabolismo Ácido Palmítico/farmacologia Cultura Primária de Células Triglicerídeos/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Cholesterol Esters); 0 (Triglycerides); 2UMI9U37CP (Oleic Acid); 2V16EO95H1 (Palmitic Acid); EC 2.3.1.20 (DGAT2 protein, human); EC 2.3.1.20 (Diacylglycerol O-Acyltransferase); EC 3.1.1.3 (Lipase); EC 3.1.1.3 (PNPLA2 protein, human) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171020 [Lr] Data última revisão: 171020 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170802 [St] Status: MEDLINE [do] DOI: 10.1111/febs.14189

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[PMID]: 28739155 [Au] Autor: Yan J; Wang G; Dang X; Guo B; Chen W; Wang T; Zeng L; Wang H; Hu Y [Ad] Endereço: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai 201203, China; School of Pharmacy, Xinxiang Medical University, 601 Jisui Avenue, Xinxiang, Henan 453003, China. [Ti] Título: Discovery of a low-systemic-exposure DGAT-1 inhibitor with a picolinoylpyrrolidine-2-carboxylic acid moiety. [So] Source: Bioorg Med Chem;25(17):4701-4714, 2017 Sep 01. [Is] ISSN: 1464-3391 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: A series of diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitors with a picolinoylpyrrolidine-2-carboxylic acid moiety were designed and synthesized. Of these compounds, compound 22 exhibited excellent DGAT-1-inhibitory activity (hDGAT-1 enzyme assay, 50% inhibitory concentration [IC ]=3.5±0.9nM) and effectively reduced the intracellular triglyceride contents in 3T3-L1, HepG2 and Caco-2 cells. A preliminary study of the plasma and tissue distributions of compound 22 in mice revealed low plasma exposure and high concentrations in different segments of the intestine and liver, which may facilitate targeting DGAT-1. Furthermore, in an acute lipid challenge test, compound 22 showed a dose-dependent inhibitory effect on high-serum triglycerides in C57/KSJ mice induced by olive oil (1, 3, and 10mg/kg, i.g.). [Mh] Termos MeSH primário: Ácidos Carboxílicos/química Diacilglicerol O-Aciltransferase/antagonistas & inibidores Inibidores Enzimáticos/química [Mh] Termos MeSH secundário: Animais Células CACO-2 Ácidos Carboxílicos/síntese química Ácidos Carboxílicos/farmacologia Diacilglicerol O-Aciltransferase/metabolismo Avaliação Pré-Clínica de Medicamentos Inibidores Enzimáticos/síntese química Inibidores Enzimáticos/farmacocinética Meia-Vida Células Hep G2 Seres Humanos Concentração Inibidora 50 Masculino Camundongos Camundongos Endogâmicos C57BL Permeabilidade/efeitos dos fármacos Pirrolidinas/química Ratos Ratos Sprague-Dawley Relação Estrutura-Atividade Distribuição Tecidual Triglicerídeos/sangue [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Carboxylic Acids); 0 (Enzyme Inhibitors); 0 (Pyrrolidines); 0 (Triglycerides); EC 2.3.1.20 (Diacylglycerol O-Acyltransferase); LJU5627FYV (pyrrolidine) [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: 170726 [St] Status: MEDLINE

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[PMID]: 28700690 [Au] Autor: Jung S; Choi M; Choi K; Kwon EB; Kang M; Kim DE; Jeong H; Kim J; Kim JH; Kim MO; Han SB; Cho S [Ad] Endereço: Anticancer Agent Research Center, Korea Research Institute of Bioscience & Biotechnology, 30 Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Cheongju-si, Chungcheongbuk-do, South Korea. [Ti] Título: Inactivation of human DGAT2 by oxidative stress on cysteine residues. [So] Source: PLoS One;12(7):e0181076, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Diacylglycerol acyltransferases (DGATs) have a crucial role in the biosynthesis of triacylglycerol (TG), the major storage form of metabolic energy in eukaryotic organisms. Even though DGAT2, one of two distinct DGATs, has a vital role in TG biosynthesis, little is known about the regulation of DGAT2 activity. In this study, we examined the role of cysteine and its oxidation in the enzymatic activity of human DGAT2 in vitro. Human DGAT2 activity was considerably inhibited not only by thiol-modifying reagents (NEM and IA) but also by ROS-related chemicals (H2O2 and ß-lapachone), while human DGAT1 and GPAT1 were little affected. Particularly, ROS-related chemicals concomitantly induced intermolecular disulfide crosslinking of human DGAT2. Both the oxidative inactivation and disulfide crosslinking were almost completely reversed by the treatment with DTT, a disulfide-reducing agent. These results clearly demonstrated the significant role of ROS-induced intermolecular crosslinking in the inactivation of human DGAT2 and also suggested DGAT2 as a redox-sensitive regulator in TG biosynthesis. [Mh] Termos MeSH primário: Cisteína/metabolismo Diacilglicerol O-Aciltransferase/metabolismo Estresse Oxidativo/fisiologia [Mh] Termos MeSH secundário: Seres Humanos Peróxido de Hidrogênio/farmacologia Estresse Oxidativo/efeitos dos fármacos Espécies Reativas de Oxigênio/metabolismo Triglicerídeos/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Reactive Oxygen Species); 0 (Triglycerides); BBX060AN9V (Hydrogen Peroxide); EC 2.3.1.20 (DGAT2 protein, human); EC 2.3.1.20 (Diacylglycerol O-Acyltransferase); K848JZ4886 (Cysteine) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170925 [Lr] Data última revisão: 170925 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170713 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0181076

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[PMID]: 28697336 [Au] Autor: Nguyen TB; Louie SM; Daniele JR; Tran Q; Dillin A; Zoncu R; Nomura DK; Olzmann JA [Ad] Endereço: Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA. [Ti] Título: DGAT1-Dependent Lipid Droplet Biogenesis Protects Mitochondrial Function during Starvation-Induced Autophagy. [So] Source: Dev Cell;42(1):9-21.e5, 2017 Jul 10. [Is] ISSN: 1878-1551 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Lipid droplets (LDs) provide an "on-demand" source of fatty acids (FAs) that can be mobilized in response to fluctuations in nutrient abundance. Surprisingly, the amount of LDs increases during prolonged periods of nutrient deprivation. Why cells store FAs in LDs during an energy crisis is unknown. Our data demonstrate that mTORC1-regulated autophagy is necessary and sufficient for starvation-induced LD biogenesis. The ER-resident diacylglycerol acyltransferase 1 (DGAT1) selectively channels autophagy-liberated FAs into new, clustered LDs that are in close proximity to mitochondria and are lipolytically degraded. However, LDs are not required for FA delivery to mitochondria but instead function to prevent acylcarnitine accumulation and lipotoxic dysregulation of mitochondria. Our data support a model in which LDs provide a lipid buffering system that sequesters FAs released during the autophagic degradation of membranous organelles, reducing lipotoxicity. These findings reveal an unrecognized aspect of the cellular adaptive response to starvation, mediated by LDs. [Mh] Termos MeSH primário: Autofagia Diacilglicerol O-Aciltransferase/metabolismo Gotículas Lipídicas/metabolismo Mitocôndrias/metabolismo [Mh] Termos MeSH secundário: Aminoácidos/deficiência Animais Autofagia/efeitos dos fármacos Carnitina/análogos & derivados Carnitina/farmacologia Seres Humanos Marcação por Isótopo Gotículas Lipídicas/efeitos dos fármacos Alvo Mecanístico do Complexo 1 de Rapamicina Camundongos Mitocôndrias/efeitos dos fármacos Modelos Biológicos Complexos Multiproteicos/metabolismo Ácido Palmítico/metabolismo Serina-Treonina Quinases TOR/metabolismo Triglicerídeos [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Amino Acids); 0 (Multiprotein Complexes); 0 (Triglycerides); 0 (acylcarnitine); 2V16EO95H1 (Palmitic Acid); EC 2.3.1.20 (Dgat1 protein, mouse); EC 2.3.1.20 (Diacylglycerol O-Acyltransferase); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1); S7UI8SM58A (Carnitine) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170712 [St] Status: MEDLINE

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[PMID]: 28665967 [Au] Autor: Ji W; Zhao M; Wang M; Yan W; Liu Y; Ren S; Lu J; Wang B; Chen L [Ad] Endereço: Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China. [Ti] Título: Effects of canagliflozin on weight loss in high-fat diet-induced obese mice. [So] Source: PLoS One;12(6):e0179960, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Canagliflozin, an inhibitor of sodium glucose co-transporter (SGLT) 2, has been shown to reduce body weight during the treatment of type 2 diabetes mellitus (T2DM). In this study, we sought to determine the role of canagliflozin in body weight loss and liver injury in obesity. C57BL/6J mice were fed a high-fat diet to simulate diet-induced obesity (DIO). Canagliflozin (15 and 60 mg/kg) was administered to DIO mice for 4 weeks. Orlistat (10 mg/kg) was used as a positive control. The body weight, liver weight, liver morphology, total cholesterol (TC) and triglyceride (TG) levels were examined. Signaling molecules, including diacylgycero1 acyltransferase-2 (DGAT2), peroxisome proliferation receptor alpha-1 (PPARα1), PPARγ1, PPARγ2 mRNA levels and the protein expression of SGLT2 were evaluated. Canagliflozin reduced body weight, especially the high-dose canagliflozin, and resulted in increased body weight loss compared with orlistat. Moreover, canagliflozin reduced the liver weight and the ratio of liver weight to body weight, lowered the serum levels of TC and TG, and ameliorated liver steatosis. During the canagliflozin treatment, SGLT2, DGAT2, PPARγ1 and PPARγ2 were inhibited, and PPARα1 was elevated in the liver tissues. This finding may explain why body weight was reduced and secondary liver injury was ameliorated in response to canagliflozin. Together, the results suggest that canagliflozin may be a potential anti-obesity strategy. [Mh] Termos MeSH primário: Canagliflozina/farmacologia Dieta Hiperlipídica Hipoglicemiantes/uso terapêutico Obesidade/terapia Perda de Peso/efeitos dos fármacos [Mh] Termos MeSH secundário: Animais Colesterol/sangue Diacilglicerol O-Aciltransferase/metabolismo Fígado/efeitos dos fármacos Fígado/patologia Camundongos Camundongos Endogâmicos C57BL Obesidade/enzimologia Obesidade/etiologia Obesidade/metabolismo Receptores Ativados por Proliferador de Peroxissomo/metabolismo Triglicerídeos/sangue [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Hypoglycemic Agents); 0 (Peroxisome Proliferator-Activated Receptors); 0 (Triglycerides); 0SAC974Z85 (Canagliflozin); 97C5T2UQ7J (Cholesterol); EC 2.3.1.20 (DGAT2 protein, mouse); EC 2.3.1.20 (Diacylglycerol O-Acyltransferase) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171002 [Lr] Data última revisão: 171002 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170701 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0179960

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MEDLINE

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[PMID]: 28641384 [Au] Autor: Santosa S; Bush NC; Jensen MD [Ad] Endereço: Endocrine Research Unit, Mayo Clinic, Rochester, Minnesota 55905. [Ti] Título: Acute Testosterone Deficiency Alters Adipose Tissue Fatty Acid Storage. [So] Source: J Clin Endocrinol Metab;102(8):3056-3064, 2017 Aug 01. [Is] ISSN: 1945-7197 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Context: Although the long-term effects of testosterone on adipose tissue lipid metabolism in men have been defined, the short-term regulation of these effects is not well understood. Objective: We examined the effects of acute testosterone withdrawal on subcutaneous abdominal and femoral adipose tissue fatty acid (FA) storage and cellular mechanisms. Design: This was a prospective, randomized trial. Setting: Mayo Clinic Clinical Research Unit. Patients or Participants: Thirty-two male volunteers ages 18 to 50 participated in these studies. Interventions: Volunteers were randomized to receive (1) no treatment (control), (2) injections (7.5 mg) of Lupron®, or (3) Lupron and testosterone (L+T) replacement for 49 days, resulting in 4 weeks of sex steroid suppression in the Lupron group. Main Outcome Measures: We measured body composition, fat cell size, adipose tissue meal FA and direct free FA storage, lipoprotein lipase (LPL), acyl coenzyme A synthetase (ACS), diacylglycerol acyltransferase activities, and CD36 content. Results: Compared with control and L+T groups, acute testosterone deficiency resulted in greater femoral adipose tissue meal FA storage rates, fasting and fed LPL activity, and ACS activity. Conclusions: These results suggest that in men, testosterone plays a tonic role in restraining FA storage in femoral adipose tissue via suppression of LPL and ACS activities. FA storage mechanisms in men appear sensitive to short-term changes in testosterone concentrations. [Mh] Termos MeSH primário: Adipócitos/efeitos dos fármacos Antagonistas de Androgênios/farmacologia Androgênios/farmacologia Composição Corporal/efeitos dos fármacos Leuprolida/farmacologia Metabolismo dos Lipídeos/efeitos dos fármacos Gordura Subcutânea/efeitos dos fármacos Testosterona/farmacologia [Mh] Termos MeSH secundário: Abdome Absorciometria de Fóton Acil Coenzima A/efeitos dos fármacos Acil Coenzima A/metabolismo Adipócitos/citologia Adolescente Adulto Western Blotting Antígenos CD36/efeitos dos fármacos Antígenos CD36/metabolismo Tamanho Celular/efeitos dos fármacos Diacilglicerol O-Aciltransferase/efeitos dos fármacos Diacilglicerol O-Aciltransferase/metabolismo Ácidos Graxos/metabolismo Ácidos Graxos não Esterificados/metabolismo Seres Humanos Lipase Lipoproteica/efeitos dos fármacos Lipase Lipoproteica/metabolismo Masculino Meia-Idade Estudos Prospectivos Gordura Subcutânea/metabolismo Coxa da Perna Adulto Jovem [Pt] Tipo de publicação: JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL [Nm] Nome de substância: 0 (Acyl Coenzyme A); 0 (Androgen Antagonists); 0 (Androgens); 0 (CD36 Antigens); 0 (Fatty Acids); 0 (Fatty Acids, Nonesterified); 3XMK78S47O (Testosterone); EC 2.3.1.20 (Diacylglycerol O-Acyltransferase); EC 3.1.1.34 (Lipoprotein Lipase); EFY6W0M8TG (Leuprolide) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170624 [St] Status: MEDLINE [do] DOI: 10.1210/jc.2017-00757

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