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[PMID]:28583767
[Au] Autor:Errico TL; Méndez-Lara KA; Santos D; Cabrerizo N; Baila-Rueda L; Metso J; Cenarro A; Pardina E; Lecube A; Jauhiainen M; Peinado-Onsurbe J; Escolà-Gil JC; Blanco-Vaca F; Julve J
[Ad] Endereço:Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau - Institut d'Investigacions Biomèdiques Sant Pau (IIB-Sant Pau), Barcelona, Spain; Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain.
[Ti] Título:LXR-dependent regulation of macrophage-specific reverse cholesterol transport is impaired in a model of genetic diabesity.
[So] Source:Transl Res;186:19-35.e5, 2017 Aug.
[Is] ISSN:1878-1810
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Diabesity and fatty liver have been associated with low levels of high-density lipoprotein cholesterol, and thus could impair macrophage-specific reverse cholesterol transport (m-RCT). Liver X receptor (LXR) plays a critical role in m-RCT. Abcg5/g8 sterol transporters, which are involved in cholesterol trafficking into bile, as well as other LXR targets, could be compromised in the livers of obese individuals. We aimed to determine m-RCT dynamics in a mouse model of diabesity, the db/db mice. These obese mice displayed a significant retention of macrophage-derived cholesterol in the liver and reduced fecal cholesterol elimination compared with nonobese mice. This was associated with a significant downregulation of the hepatic LXR targets, including Abcg5/g8. Pharmacologic induction of LXR promoted the delivery of total tracer output into feces in db/db mice, partly due to increased liver and small intestine Abcg5/Abcg8 gene expression. Notably, a favorable upregulation of the hepatic levels of ABCG5/G8 and NR1H3 was also observed postoperatively in morbidly obese patients, suggesting a similar LXR impairment in these patients. In conclusion, our data show that downregulation of the LXR axis impairs cholesterol transfer from macrophages to feces in db/db mice, whereas the induction of the LXR axis partly restores impaired m-RCT by elevating the liver and small intestine expressions of Abcg5/g8.
[Mh] Termos MeSH primário: Colesterol/metabolismo
Diabetes Mellitus/genética
Diabetes Mellitus/metabolismo
Receptores X do Fígado/metabolismo
Macrófagos/metabolismo
[Mh] Termos MeSH secundário: Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética
Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo
Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética
Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo
Animais
Transporte Biológico
Lipoproteínas/genética
Lipoproteínas/metabolismo
Receptores X do Fígado/genética
Masculino
Camundongos
Obesidade
Transdução de Sinais
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ABCG5 protein, mouse); 0 (ABCG8 protein, mouse); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 5); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 8); 0 (Lipoproteins); 0 (Liver X Receptors); 97C5T2UQ7J (Cholesterol)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170607
[St] Status:MEDLINE


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[PMID]:28065787
[Au] Autor:de Boer JF; Schonewille M; Boesjes M; Wolters H; Bloks VW; Bos T; van Dijk TH; Jurdzinski A; Boverhof R; Wolters JC; Kuivenhoven JA; van Deursen JM; Oude Elferink RP; Moschetta A; Kremoser C; Verkade HJ; Kuipers F; Groen AK
[Ad] Endereço:Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address: j.f.de.boer@umcg.nl.
[Ti] Título:Intestinal Farnesoid X Receptor Controls Transintestinal Cholesterol Excretion in Mice.
[So] Source:Gastroenterology;152(5):1126-1138.e6, 2017 Apr.
[Is] ISSN:1528-0012
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND & AIMS: The role of the intestine in the maintenance of cholesterol homeostasis increasingly is recognized. Fecal excretion of cholesterol is the last step in the atheroprotective reverse cholesterol transport pathway, to which biliary and transintestinal cholesterol excretion (TICE) contribute. The mechanisms controlling the flux of cholesterol through the TICE pathway, however, are poorly understood. We aimed to identify mechanisms that regulate and stimulate TICE. METHODS: We performed studies with C57Bl/6J mice, as well as with mice with intestine-specific knockout of the farnesoid X receptor (FXR), mice that express an FXR transgene specifically in the intestine, and ABCG8-knockout mice. Mice were fed a control diet or a diet supplemented with the FXR agonist PX20606, with or without the cholesterol absorption inhibitor ezetimibe. Some mice with intestine-specific knockout of FXR were given daily injections of fibroblast growth factor (FGF)19. To determine fractional cholesterol absorption, mice were given intravenous injections of cholesterol D and oral cholesterol D . Mice were given C-acetate in drinking water for measurement of cholesterol synthesis. Bile cannulations were performed and biliary cholesterol secretion rates were assessed. In a separate set of experiments, bile ducts of male Wistar rats were exteriorized, allowing replacement of endogenous bile by a model bile. RESULTS: In mice, we found TICE to be regulated by intestinal FXR via induction of its target gene Fgf15 (FGF19 in rats and human beings). Stimulation of this pathway caused mice to excrete up to 60% of their total cholesterol content each day. PX20606 and FGF19 each increased the ratio of muricholate:cholate in bile, inducing a more hydrophilic bile salt pool. The altered bile salt pool stimulated robust secretion of cholesterol into the intestinal lumen via the sterol-exporting heterodimer adenosine triphosphate binding cassette subfamily G member 5/8 (ABCG5/G8). Of note, the increase in TICE induced by PX20606 was independent of changes in cholesterol absorption. CONCLUSIONS: Hydrophilicity of the bile salt pool, controlled by FXR and FGF15/19, is an important determinant of cholesterol removal via TICE. Strategies that alter bile salt pool composition might be developed for the prevention of cardiovascular disease. Transcript profiling: http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=irsrayeohfcntqx&acc=GSE74101.
[Mh] Termos MeSH primário: Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética
Ácidos e Sais Biliares/metabolismo
Colesterol/secreção
Fatores de Crescimento de Fibroblastos/metabolismo
Eliminação Intestinal/genética
Mucosa Intestinal/secreção
Lipoproteínas/genética
Receptores Citoplasmáticos e Nucleares/genética
[Mh] Termos MeSH secundário: Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo
Animais
Anticolesterolemiantes/farmacologia
Benzoatos/farmacologia
Ductos Biliares
Colesterol/metabolismo
Ezetimiba/farmacologia
Eliminação Intestinal/efeitos dos fármacos
Mucosa Intestinal/efeitos dos fármacos
Mucosa Intestinal/metabolismo
Intestinos/efeitos dos fármacos
Intestinos/metabolismo
Isoxazóis/farmacologia
Lipoproteínas/metabolismo
Masculino
Camundongos
Camundongos Knockout
Camundongos Transgênicos
Ratos
Ratos Wistar
Receptores Citoplasmáticos e Nucleares/agonistas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (4-(2-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl)methoxy)phenyl)cyclopropyl)benzoic acid); 0 (ABCG8 protein, mouse); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 8); 0 (Anticholesteremic Agents); 0 (Benzoates); 0 (Bile Acids and Salts); 0 (Isoxazoles); 0 (Lipoproteins); 0 (Receptors, Cytoplasmic and Nuclear); 0 (farnesoid X-activated receptor); 0 (fibroblast growth factor 15, mouse); 62031-54-3 (Fibroblast Growth Factors); 97C5T2UQ7J (Cholesterol); EOR26LQQ24 (Ezetimibe)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170613
[Lr] Data última revisão:
170613
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170110
[St] Status:MEDLINE


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[PMID]:26851362
[Au] Autor:Heverin M; Ali Z; Olin M; Tillander V; Joibari MM; Makoveichuk E; Leitersdorf E; Warner M; Olivercrona G; Gustafsson JÅ; Björkhem I
[Ad] Endereço:Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden.
[Ti] Título:On the regulatory importance of 27-hydroxycholesterol in mouse liver.
[So] Source:J Steroid Biochem Mol Biol;169:10-21, 2017 May.
[Is] ISSN:1879-1220
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:27-Hydroxycholesterol (27OH) is a strong suppressor of cholesterol synthesis and a weak activator of LXR in vitro. The regulatory importance of 27OH in vivo is controversial. Here we utilized male mice with increased levels of 27OH either due to increased production (CYP27A1 transgenic mice) or reduced metabolism (Cyp7b1-/- mice). We also used mice lacking 27OH due to a knockout of Cyp27a1. The latter mice were treated with cholic acid to compensate for reduced bile acid synthesis. The effects of the different levels of 27OH on Srebp- and other LXR-regulated genes in the liver were investigated. In the liver of CYP27tg mice we found a modest increase of the mRNA levels corresponding to the LXR target genes Cyp7b1 and Abca1. A number of other LXR-regulated genes were not affected. The effect on Abca1 mRNA was not seen in the liver of Cyp7b1-/- mice. There were little or no effects on cholesterol synthesis. In the liver of the Cyp27-/- mice treated with 0.025% cholic acid there was no significant effect of the knockout on the LXR target genes. In a previous work triple-knockout mice deficient in the biosynthesis of 24S-hydroxycholesterol, 25-hydroxycholesterol and 27OH were shown to have impaired response to dietary cholesterol, suggesting side-chain oxidized oxysterols to be mediators in cholesterol-induced effects on LXR target genes at a transcriptional level (Chen W. et al., Cell Metab. 5 (2007) 73-79). The hydroxylated oxysterol responsible for the effect was not defined. We show here that treatment of wildtype mice with dietary cholesterol under the same conditions as in the above study induced the LXR target genes Lpl, Abcg8 and Srebp1c in wild type mice but failed to activate the same genes in mice lacking 27-hydroxycholesterol due to a knockout of Cyp27. We failed to demonstrate the above effects at the protein level (Abcg8) or at the activity level (Lpl). The results suggest that 27OH is not an important regulator of Srebp- or LXR regulated genes under basal conditions in mouse liver. On the other hand 27OH appears to mediate cholesterol-induced effects on some LXR target genes at a transcriptional level under some in vivo conditions.
[Mh] Termos MeSH primário: Hidroxicolesteróis/metabolismo
Fígado/metabolismo
[Mh] Termos MeSH secundário: Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo
Animais
Colestanotriol 26-Mono-Oxigenase/genética
Família 7 do Citocromo P450/genética
Perfilação da Expressão Gênica
Lipase Lipoproteica/metabolismo
Lipoproteínas/metabolismo
Receptores X do Fígado/metabolismo
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Receptores Citoplasmáticos e Nucleares/metabolismo
Esteroide Hidroxilases/genética
Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
Transcrição Genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ABCG8 protein, mouse); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 8); 0 (Hydroxycholesterols); 0 (Lipoproteins); 0 (Liver X Receptors); 0 (Receptors, Cytoplasmic and Nuclear); 0 (Srebf1 protein, mouse); 0 (Sterol Regulatory Element Binding Protein 1); 6T2NA6P5SQ (27-hydroxycholesterol); EC 1.14.- (Steroid Hydroxylases); EC 1.14.13.100 (Cyp7b1 protein, mouse); EC 1.14.14.23 (Cytochrome P450 Family 7); EC 1.14.15.15 (Cholestanetriol 26-Monooxygenase); EC 1.14.15.15 (Cyp27a1 protein, mouse); EC 3.1.1.34 (Lipoprotein Lipase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170713
[Lr] Data última revisão:
170713
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160207
[St] Status:MEDLINE


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[PMID]:28426890
[Au] Autor:Zubair N; Graff M; Luis Ambite J; Bush WS; Kichaev G; Lu Y; Manichaikul A; Sheu WH; Absher D; Assimes TL; Bielinski SJ; Bottinger EP; Buzkova P; Chuang LM; Chung RH; Cochran B; Dumitrescu L; Gottesman O; Haessler JW; Haiman C; Heiss G; Hsiung CA; Hung YJ; Hwu CM; Juang JJ; Le Marchand L; Lee IT; Lee WJ; Lin LA; Lin D; Lin SY; Mackey RH; Martin LW; Pasaniuc B; Peters U; Predazzi I; Quertermous T; Reiner AP; Robinson J; Rotter JI; Ryckman KK; Schreiner PJ; Stahl E; Tao R; Tsai MY; Waite LL; Wang TD; Buyske S; Ida Chen YD; Cheng I
[Ad] Endereço:Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
[Ti] Título:Fine-mapping of lipid regions in global populations discovers ethnic-specific signals and refines previously identified lipid loci.
[So] Source:Hum Mol Genet;25(24):5500-5512, 2016 Dec 15.
[Is] ISSN:1460-2083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Genome-wide association studies have identified over 150 loci associated with lipid traits, however, no large-scale studies exist for Hispanics and other minority populations. Additionally, the genetic architecture of lipid-influencing loci remains largely unknown. We performed one of the most racially/ethnically diverse fine-mapping genetic studies of HDL-C, LDL-C, and triglycerides to-date using SNPs on the MetaboChip array on 54,119 individuals: 21,304 African Americans, 19,829 Hispanic Americans, 12,456 Asians, and 530 American Indians. The majority of signals found in these groups generalize to European Americans. While we uncovered signals unique to racial/ethnic populations, we also observed systematically consistent lipid associations across these groups. In African Americans, we identified three novel signals associated with HDL-C (LPL, APOA5, LCAT) and two associated with LDL-C (ABCG8, DHODH). In addition, using this population, we refined the location for 16 out of the 58 known MetaboChip lipid loci. These results can guide tailored screening efforts, reveal population-specific responses to lipid-lowering medications, and aid in the development of new targeted drug therapies.
[Mh] Termos MeSH primário: HDL-Colesterol/genética
LDL-Colesterol/genética
Estudo de Associação Genômica Ampla
Lipídeos/genética
[Mh] Termos MeSH secundário: Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética
Afroamericanos/genética
Apolipoproteína A-V/genética
Grupo com Ancestrais do Continente Asiático/genética
Feminino
Hispano-Americanos/genética
Seres Humanos
Índios Norte-Americanos/genética
Lipase Lipoproteica/genética
Masculino
Triglicerídeos/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ABCG8 protein, human); 0 (APOA5 protein, human); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 8); 0 (Apolipoprotein A-V); 0 (Cholesterol, HDL); 0 (Cholesterol, LDL); 0 (Lipids); 0 (Triglycerides); EC 3.1.1.34 (LPL protein, human); EC 3.1.1.34 (Lipoprotein Lipase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170609
[Lr] Data última revisão:
170609
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170421
[St] Status:MEDLINE
[do] DOI:10.1093/hmg/ddw358


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[PMID]:27981300
[Au] Autor:Zimmermann A; Popp RA; Al-Khzouz C; Bucerzan S; Nascu I; Leucuta D; Galle PR; Grigorescu-Sido P
[Ad] Endereço:1st Clinic and Polyclinic of Internal Medicine, Dept. Endocrinology and Metabolic Diseases, University of Mainz, Mainz, Germany. zimmeran@uni-mainz.de.
[Ti] Título:Cholelithiasis in Patients with Gaucher Disease type 1: Risk Factors and the Role of ABCG5/ABCG8 Gene Variants.
[So] Source:J Gastrointestin Liver Dis;25(4):447-455, 2016 12.
[Is] ISSN:1842-1121
[Cp] País de publicação:Romania
[La] Idioma:eng
[Ab] Resumo:BACKGROUND AND AIM: Patients with Gaucher disease type 1 (GD1) show an altered lipid profile and a certain degree of insulin resistance, which might contribute to cholelithiasis (CL) and could possibly be associated with ABCG5/ABCG8 gene variants. We aimed to investigate the prevalence of CL in Caucasian adult patients with GD1 and the possible risk factors, including gene variants of the ABCG5/ABCG8 genes. METHODS: 61 Caucasian patients with GD1 (38 female/23male), aged 18-62 years and 61 healthy subjects matched for age, gender and BMI, without CL, for comparison of lipid profiles. Data before start of enzyme replacement therapy (ERT) were recorded: clinical, haematological, severity parameters, splenectomy, genotype. Fasting lipid profiles before ERT, glycemia, insulinaemia, HOMA-IR at the last visit were documented. Genotyping for the gene variants D19H, Y54C, T400K, A632V (ABCG8); Q604E (ABCG5) was performed. RESULTS: CL occurred in 45.9% of patients. Risk factors were: age, family history of CL, higher BMI values, LDL-cholesterol (LDL-C), disease severity, splenectomy. A specific dyslipidemia was found in patients vs. controls. Total serum cholesterol (TC) and LDL-C were higher in patients with CL than in those without; no obvious influence of insulin-resistance to lithogenesis was found. Patients with the GG genotype of D19H and the CC genotype of T400K (ABCG8 gene) had significantly higher levels of TC and LDL-C. CONCLUSION: Patients with GD1 showed an increased prevalence of CL, which was associated with common and disease-specific risk factors. Starting ERT soon after clinical onset and avoiding splenectomy might reduce the risk of CL in GD1.
[Mh] Termos MeSH primário: Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética
Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética
Colelitíase/genética
Doença de Gaucher/genética
Variação Genética
Lipoproteínas/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Estudos de Casos e Controles
Colelitíase/diagnóstico
Colelitíase/epidemiologia
Estudos Transversais
Terapia de Reposição de Enzimas
Grupo com Ancestrais do Continente Europeu/genética
Feminino
Doença de Gaucher/diagnóstico
Doença de Gaucher/tratamento farmacológico
Doença de Gaucher/epidemiologia
Frequência do Gene
Estudos de Associação Genética
Predisposição Genética para Doença
Glucosilceramidase/uso terapêutico
Heterozigoto
Homozigoto
Seres Humanos
Masculino
Meia-Idade
Fenótipo
Prevalência
Fatores de Risco
Romênia/epidemiologia
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; OBSERVATIONAL STUDY
[Nm] Nome de substância:
0 (ABCG5 protein, human); 0 (ABCG8 protein, human); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 5); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 8); 0 (Lipoproteins); EC 3.2.1.45 (Glucosylceramidase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170823
[Lr] Data última revisão:
170823
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161217
[St] Status:MEDLINE
[do] DOI:10.15403/jgld.2014.1121.254.zim


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[PMID]:27818259
[Au] Autor:Jakulj L; van Dijk TH; de Boer JF; Kootte RS; Schonewille M; Paalvast Y; Boer T; Bloks VW; Boverhof R; Nieuwdorp M; Beuers UH; Stroes ES; Groen AK
[Ad] Endereço:Department of Vascular Medicine, Academic Medical Center, Amsterdam 1105AZ, the Netherlands.
[Ti] Título:Transintestinal Cholesterol Transport Is Active in Mice and Humans and Controls Ezetimibe-Induced Fecal Neutral Sterol Excretion.
[So] Source:Cell Metab;24(6):783-794, 2016 Dec 13.
[Is] ISSN:1932-7420
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Except for conversion to bile salts, there is no major cholesterol degradation pathway in mammals. Efficient excretion from the body is therefore a crucial element in cholesterol homeostasis. Yet, the existence and importance of cholesterol degradation pathways in humans is a matter of debate. We quantified cholesterol fluxes in 15 male volunteers using a cholesterol balance approach. Ten participants repeated the protocol after 4 weeks of treatment with ezetimibe, an inhibitor of intestinal and biliary cholesterol absorption. Under basal conditions, about 65% of daily fecal neutral sterol excretion was bile derived, with the remainder being contributed by direct transintestinal cholesterol excretion (TICE). Surprisingly, ezetimibe induced a 4-fold increase in cholesterol elimination via TICE. Mouse studies revealed that most of ezetimibe-induced TICE flux is mediated by the cholesterol transporter Abcg5/Abcg8. In conclusion, TICE is active in humans and may serve as a novel target to stimulate cholesterol elimination in patients at risk for cardiovascular disease.
[Mh] Termos MeSH primário: Colesterol/metabolismo
Ezetimiba/farmacologia
Fezes/química
Intestinos/metabolismo
[Mh] Termos MeSH secundário: Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/deficiência
Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo
Adulto
Animais
Bile/química
Ácidos e Sais Biliares/metabolismo
Transporte Biológico/efeitos dos fármacos
Colesterol/sangue
Feminino
Seres Humanos
Intestinos/efeitos dos fármacos
Cinética
Lipoproteínas/deficiência
Lipoproteínas/metabolismo
Masculino
Camundongos Endogâmicos C57BL
Meia-Idade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ABCG8 protein, mouse); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 8); 0 (Bile Acids and Salts); 0 (Lipoproteins); 97C5T2UQ7J (Cholesterol); EOR26LQQ24 (Ezetimibe)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170803
[Lr] Data última revisão:
170803
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161108
[St] Status:MEDLINE


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[PMID]:27383786
[Au] Autor:Hsieh J; Koseki M; Molusky MM; Yakushiji E; Ichi I; Westerterp M; Iqbal J; Chan RB; Abramowicz S; Tascau L; Takiguchi S; Yamashita S; Welch CL; Di Paolo G; Hussain MM; Lefkowitch JH; Rader DJ; Tall AR
[Ad] Endereço:Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA.
[Ti] Título:TTC39B deficiency stabilizes LXR reducing both atherosclerosis and steatohepatitis.
[So] Source:Nature;535(7611):303-7, 2016 07 14.
[Is] ISSN:1476-4687
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Cellular mechanisms that mediate steatohepatitis, an increasingly prevalent condition in the Western world for which no therapies are available, are poorly understood. Despite the fact that its synthetic agonists induce fatty liver, the liver X receptor (LXR) transcription factor remains a target of interest because of its anti-atherogenic, cholesterol removal, and anti-inflammatory activities. Here we show that tetratricopeptide repeat domain protein 39B (Ttc39b, C9orf52) (T39), a high-density lipoprotein gene discovered in human genome-wide association studies, promotes the ubiquitination and degradation of LXR. Chow-fed mice lacking T39 (T39(-/-)) display increased high-density lipoprotein cholesterol levels associated with increased enterocyte ATP-binding cassette transporter A1 (Abca1) expression and increased LXR protein without change in LXR messenger RNA. When challenged with a high fat/high cholesterol/bile salt diet, T39(-/-) mice or mice with hepatocyte-specific T39 deficiency show increased hepatic LXR protein and target gene expression, and unexpectedly protection from steatohepatitis and death. Mice fed a Western-type diet and lacking low-density lipoprotein receptor (Ldlr(-/-)T39(-/-)) show decreased fatty liver, increased high-density lipoprotein, decreased low-density lipoprotein, and reduced atherosclerosis. In addition to increasing hepatic Abcg5/8 expression and limiting dietary cholesterol absorption, T39 deficiency inhibits hepatic sterol regulatory element-binding protein 1 (SREBP-1, ADD1) processing. This is explained by an increase in microsomal phospholipids containing polyunsaturated fatty acids, linked to an LXRα-dependent increase in expression of enzymes mediating phosphatidylcholine biosynthesis and incorporation of polyunsaturated fatty acids into phospholipids. The preservation of endogenous LXR protein activates a beneficial profile of gene expression that promotes cholesterol removal and inhibits lipogenesis. T39 inhibition could be an effective strategy for reducing both steatohepatitis and atherosclerosis.
[Mh] Termos MeSH primário: Aterosclerose/genética
Fígado Gorduroso/genética
Lipoproteínas HDL/deficiência
Lipoproteínas HDL/genética
Receptores Nucleares Órfãos/metabolismo
[Mh] Termos MeSH secundário: Transportador 1 de Cassete de Ligação de ATP/metabolismo
Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP
Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP
Transportadores de Cassetes de Ligação de ATP/metabolismo
Animais
Aterosclerose/prevenção & controle
Aterosclerose/terapia
Ácidos e Sais Biliares/metabolismo
Colesterol na Dieta/metabolismo
HDL-Colesterol/metabolismo
Dieta Hiperlipídica
Ácidos Graxos Insaturados/metabolismo
Fígado Gorduroso/prevenção & controle
Fígado Gorduroso/terapia
Feminino
Regulação da Expressão Gênica
Hepatócitos/metabolismo
Ligantes
Lipogênese/genética
Lipoproteínas/metabolismo
Lipoproteínas HDL/metabolismo
Lipoproteínas LDL/metabolismo
Receptores X do Fígado
Masculino
Camundongos
Receptores Nucleares Órfãos/genética
Fosfatidilcolinas/biossíntese
Fosfatidilcolinas/metabolismo
Estabilidade Proteica
Proteólise
Receptores de LDL/deficiência
Receptores de LDL/genética
Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
Ubiquitinação
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (ABCA1 protein, mouse); 0 (ABCG5 protein, mouse); 0 (ABCG8 protein, mouse); 0 (ATP Binding Cassette Transporter 1); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 5); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 8); 0 (Bile Acids and Salts); 0 (Cholesterol, Dietary); 0 (Cholesterol, HDL); 0 (Fatty Acids, Unsaturated); 0 (Ligands); 0 (Lipoproteins); 0 (Lipoproteins, HDL); 0 (Lipoproteins, LDL); 0 (Liver X Receptors); 0 (NR1H3 protein, human); 0 (Nr1h3 protein, mouse); 0 (Orphan Nuclear Receptors); 0 (Phosphatidylcholines); 0 (Receptors, LDL); 0 (Srebf1 protein, mouse); 0 (Sterol Regulatory Element Binding Protein 1); 0 (TTC39B protein, mouse)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:170324
[Lr] Data última revisão:
170324
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160708
[St] Status:MEDLINE
[do] DOI:10.1038/nature18628


  8 / 270 MEDLINE  
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[PMID]:27144356
[Au] Autor:Lee JY; Kinch LN; Borek DM; Wang J; Wang J; Urbatsch IL; Xie XS; Grishin NV; Cohen JC; Otwinowski Z; Hobbs HH; Rosenbaum DM
[Ad] Endereço:Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
[Ti] Título:Crystal structure of the human sterol transporter ABCG5/ABCG8.
[So] Source:Nature;533(7604):561-4, 2016 05 26.
[Is] ISSN:1476-4687
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:ATP binding cassette (ABC) transporters play critical roles in maintaining sterol balance in higher eukaryotes. The ABCG5/ABCG8 heterodimer (G5G8) mediates excretion of neutral sterols in liver and intestines. Mutations disrupting G5G8 cause sitosterolaemia, a disorder characterized by sterol accumulation and premature atherosclerosis. Here we use crystallization in lipid bilayers to determine the X-ray structure of human G5G8 in a nucleotide-free state at 3.9 Å resolution, generating the first atomic model of an ABC sterol transporter. The structure reveals a new transmembrane fold that is present in a large and functionally diverse superfamily of ABC transporters. The transmembrane domains are coupled to the nucleotide-binding sites by networks of interactions that differ between the active and inactive ATPases, reflecting the catalytic asymmetry of the transporter. The G5G8 structure provides a mechanistic framework for understanding sterol transport and the disruptive effects of mutations causing sitosterolaemia.
[Mh] Termos MeSH primário: Transportadores de Cassetes de Ligação de ATP/química
Lipoproteínas/química
Esteróis/metabolismo
[Mh] Termos MeSH secundário: Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP
Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP
Transportadores de Cassetes de Ligação de ATP/genética
Transportadores de Cassetes de Ligação de ATP/metabolismo
Adenosina Trifosfatases/metabolismo
Sequência de Aminoácidos
Sítios de Ligação
Biocatálise
Cristalografia por Raios X
Seres Humanos
Hipercolesterolemia/genética
Enteropatias/genética
Bicamadas Lipídicas/química
Bicamadas Lipídicas/metabolismo
Erros Inatos do Metabolismo Lipídico/genética
Lipoproteínas/genética
Lipoproteínas/metabolismo
Modelos Moleculares
Dados de Sequência Molecular
Nucleotídeos
Fitosteróis/efeitos adversos
Fitosteróis/genética
Dobramento de Proteína
Multimerização Proteica
Estrutura Terciária de Proteína
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (ABCG5 protein, human); 0 (ABCG8 protein, human); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 5); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 8); 0 (Lipid Bilayers); 0 (Lipoproteins); 0 (Nucleotides); 0 (Phytosterols); 0 (Sterols); EC 3.6.1.- (Adenosine Triphosphatases)
[Em] Mês de entrada:1606
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160505
[St] Status:MEDLINE
[do] DOI:10.1038/nature17666


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[PMID]:27094239
[Au] Autor:Joshi AD; Andersson C; Buch S; Stender S; Noordam R; Weng LC; Weeke PE; Auer PL; Boehm B; Chen C; Choi H; Curhan G; Denny JC; De Vivo I; Eicher JD; Ellinghaus D; Folsom AR; Fuchs C; Gala M; Haessler J; Hofman A; Hu F; Hunter DJ; Janssen HL; Kang JH; Kooperberg C; Kraft P; Kratzer W; Lieb W; Lutsey PL; Darwish Murad S; Nordestgaard BG; Pasquale LR; Reiner AP; Ridker PM; Rimm E; Rose LM; Shaffer CM; Schafmayer C; Tamimi RM; Uitterlinden AG; Völker U; Völzke H; Wakabayashi Y; Wiggs JL; Zhu J; Roden DM; Stricker BH; Tang W; Teumer A
[Ad] Endereço:Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Clinical and Translational Epidemiology Unit, Depa
[Ti] Título:Four Susceptibility Loci for Gallstone Disease Identified in a Meta-analysis of Genome-Wide Association Studies.
[So] Source:Gastroenterology;151(2):351-363.e28, 2016 Aug.
[Is] ISSN:1528-0012
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND & AIMS: A genome-wide association study (GWAS) of 280 cases identified the hepatic cholesterol transporter ABCG8 as a locus associated with risk for gallstone disease, but findings have not been reported from any other GWAS of this phenotype. We performed a large-scale, meta-analysis of GWASs of individuals of European ancestry with available prior genotype data, to identify additional genetic risk factors for gallstone disease. METHODS: We obtained per-allele odds ratio (OR) and standard error estimates using age- and sex-adjusted logistic regression models within each of the 10 discovery studies (8720 cases and 55,152 controls). We performed an inverse variance weighted, fixed-effects meta-analysis of study-specific estimates to identify single-nucleotide polymorphisms that were associated independently with gallstone disease. Associations were replicated in 6489 cases and 62,797 controls. RESULTS: We observed independent associations for 2 single-nucleotide polymorphisms at the ABCG8 locus: rs11887534 (OR, 1.69; 95% confidence interval [CI], 1.54-1.86; P = 2.44 × 10(-60)) and rs4245791 (OR, 1.27; P = 1.90 × 10(-34)). We also identified and/or replicated associations for rs9843304 in TM4SF4 (OR, 1.12; 95% CI, 1.08-1.16; P = 6.09 × 10(-11)), rs2547231 in SULT2A1 (encodes a sulfoconjugation enzyme that acts on hydroxysteroids and cholesterol-derived sterol bile acids) (OR, 1.17; 95% CI, 1.12-1.21; P = 2.24 × 10(-10)), rs1260326 in glucokinase regulatory protein (OR, 1.12; 95% CI, 1.07-1.17; P = 2.55 × 10(-10)), and rs6471717 near CYP7A1 (encodes an enzyme that catalyzes conversion of cholesterol to primary bile acids) (OR, 1.11; 95% CI, 1.08-1.15; P = 8.84 × 10(-9)). Among individuals of African American and Hispanic American ancestry, rs11887534 and rs4245791 were associated positively with gallstone disease risk, whereas the association for the rs1260326 variant was inverse. CONCLUSIONS: In this large-scale GWAS of gallstone disease, we identified 4 loci in genes that have putative functions in cholesterol metabolism and transport, and sulfonylation of bile acids or hydroxysteroids.
[Mh] Termos MeSH primário: Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética
Cálculos Biliares/genética
Loci Gênicos/genética
Predisposição Genética para Doença
[Mh] Termos MeSH secundário: Adulto
Afroamericanos/genética
Idoso
Estudos de Casos e Controles
Colesterol/metabolismo
Grupo com Ancestrais do Continente Europeu/genética
Feminino
Estudo de Associação Genômica Ampla
Hispano-Americanos/genética
Seres Humanos
Metabolismo dos Lipídeos/genética
Modelos Logísticos
Masculino
Meia-Idade
Razão de Chances
Fenótipo
Polimorfismo de Nucleotídeo Único
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS
[Nm] Nome de substância:
0 (ABCG8 protein, human); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 8); 97C5T2UQ7J (Cholesterol)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170801
[Lr] Data última revisão:
170801
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160421
[St] Status:MEDLINE


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[PMID]:27014967
[Au] Autor:Wang HH; Li X; Patel SB; Wang DQ
[Ad] Endereço:Department of Medicine, Liver Center and Gastroenterology Division, Beth Israel Deaconess Medical Center, Harvard Medical School and Harvard Digestive Diseases Center, Boston, MA.
[Ti] Título:Evidence that the adenosine triphosphate-binding cassette G5/G8-independent pathway plays a determinant role in cholesterol gallstone formation in mice.
[So] Source:Hepatology;64(3):853-64, 2016 Sep.
[Is] ISSN:1527-3350
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:UNLABELLED: The adenosine triphosphate-binding cassette (ABC) sterol transporter, Abcg5/g8, is Lith9 in mice, and two gallstone-associated variants in ABCG5/G8 have been identified in humans. Although ABCG5/G8 plays a critical role in determining hepatic sterol secretion, cholesterol is still secreted to bile in sitosterolemic patients with a defect in either ABCG5 or ABCG8 and in either Abcg5/g8 double- or single-knockout mice. We hypothesize that in the defect of ABCG5/G8, an ABCG5/G8-independent pathway is essential for regulating hepatic secretion of biliary sterols, which is independent of the lithogenic mechanism of the ABCG5/G8 pathway. To elucidate the effect of the ABCG5/G8-independent pathway on cholelithogenesis, we investigated the biliary and gallstone characteristics in male wild-type (WT), ABCG5(-/-)/G8(-/-), and ABCG8 (-/-) mice fed a lithogenic diet or varying amounts of cholesterol, treated with a liver X receptor (LXR) agonist, or injected intravenously with [(3) H]sitostanol- and [(14) C]cholesterol-labeled high-density lipoprotein (HDL). We found that ABCG5(-/-)/G8(-/-) and ABCG8 (-/-) mice displayed the same biliary and gallstone phenotypes. Although both groups of knockout mice showed a significant reduction in hepatic cholesterol output compared to WT mice, they still formed gallstones. The LXR agonist significantly increased biliary cholesterol secretion and gallstones in WT, but not ABCG5(-/-)/G8(-/-) or ABCG8 (-/-), mice. The 6-hour recovery of [(14) C]cholesterol in hepatic bile was significantly lower in both groups of knockout mice than in WT mice and [(3) H]sitostanol was detected in WT, but not ABCG5(-/-)/G8(-/-) or ABCG8 (-/-), mice. CONCLUSIONS: The ABCG5/G8-independent pathway plays an important role in regulating biliary cholesterol secretion, the transport of HDL-derived cholesterol from plasma to bile, and gallstone formation, which works independently of the ABCG5/G8 pathway. Further studies are needed to observe whether this pathway is also operational in humans. (Hepatology 2016;64:853-864).
[Mh] Termos MeSH primário: Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética
Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética
Colesterol/secreção
Cálculos Biliares/etiologia
Lipoproteínas/genética
[Mh] Termos MeSH secundário: Animais
Bile/metabolismo
Ácidos e Sais Biliares/metabolismo
Colesterol/metabolismo
Feminino
Vesícula Biliar/fisiologia
Cálculos Biliares/metabolismo
Hidrocarbonetos Fluorados
Metabolismo dos Lipídeos
Masculino
Camundongos Endogâmicos C57BL
Camundongos Knockout
Sulfonamidas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ABCG5 protein, mouse); 0 (ABCG8 protein, mouse); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 5); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 8); 0 (Bile Acids and Salts); 0 (Hydrocarbons, Fluorinated); 0 (Lipoproteins); 0 (Sulfonamides); 0 (TO-901317); 97C5T2UQ7J (Cholesterol)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170802
[Lr] Data última revisão:
170802
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160326
[St] Status:MEDLINE
[do] DOI:10.1002/hep.28570



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