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[PMID]:27770636
[Au] Autor:Mez J; Chung J; Jun G; Kriegel J; Bourlas AP; Sherva R; Logue MW; Barnes LL; Bennett DA; Buxbaum JD; Byrd GS; Crane PK; Ertekin-Taner N; Evans D; Fallin MD; Foroud T; Goate A; Graff-Radford NR; Hall KS; Kamboh MI; Kukull WA; Larson EB; Manly JJ; Haines JL; Mayeux R; Pericak-Vance MA; Schellenberg GD; Lunetta KL; Farrer LA; Alzheimer's Disease Genetics Consortium
[Ad] Endereço:Department of Neurology, Boston University School of Medicine, Boston, MA, USA; Alzheimer's Disease and CTE Center, Boston University School of Medicine, Boston, MA, USA. Electronic address: jessemez@bu.edu.
[Ti] Título:Two novel loci, COBL and SLC10A2, for Alzheimer's disease in African Americans.
[So] Source:Alzheimers Dement;13(2):119-129, 2017 Feb.
[Is] ISSN:1552-5279
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: African Americans' (AAs) late-onset Alzheimer's disease (LOAD) genetic risk profile is incompletely understood. Including clinical covariates in genetic analyses using informed conditioning might improve study power. METHODS: We conducted a genome-wide association study (GWAS) in AAs employing informed conditioning in 1825 LOAD cases and 3784 cognitively normal controls. We derived a posterior liability conditioned on age, sex, diabetes status, current smoking status, educational attainment, and affection status, with parameters informed by external prevalence information. We assessed association between the posterior liability and a genome-wide set of single-nucleotide polymorphisms (SNPs), controlling for APOE and ABCA7, identified previously in a LOAD GWAS of AAs. RESULTS: Two SNPs at novel loci, rs112404845 (P = 3.8 × 10 ), upstream of COBL, and rs16961023 (P = 4.6 × 10 ), downstream of SLC10A2, obtained genome-wide significant evidence of association with the posterior liability. DISCUSSION: An informed conditioning approach can detect LOAD genetic associations in AAs not identified by traditional GWAS.
[Mh] Termos MeSH primário: Afroamericanos/genética
Doença de Alzheimer/etnologia
Doença de Alzheimer/genética
Loci Gênicos
Proteínas dos Microfilamentos/genética
Transportadores de Ânions Orgânicos Dependentes de Sódio/genética
Polimorfismo de Nucleotídeo Único
Simportadores/genética
[Mh] Termos MeSH secundário: Transportadores de Cassetes de Ligação de ATP/genética
Idoso
Idoso de 80 Anos ou mais
Apolipoproteínas E/genética
Complicações do Diabetes/etnologia
Complicações do Diabetes/genética
Escolaridade
Feminino
Predisposição Genética para Doença
Estudo de Associação Genômica Ampla
Seres Humanos
Masculino
Prevalência
Fumar/etnologia
Fumar/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ABCA7 protein, human); 0 (ATP-Binding Cassette Transporters); 0 (Apolipoproteins E); 0 (Cobl protein, human); 0 (Microfilament Proteins); 0 (Organic Anion Transporters, Sodium-Dependent); 0 (Symporters); 145420-23-1 (sodium-bile acid cotransporter)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161023
[St] Status:MEDLINE


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[PMID]:28938430
[Au] Autor:Kersseboom S; van Gucht ALM; van Mullem A; Brigante G; Farina S; Carlsson B; Donkers JM; van de Graaf SFJ; Peeters RP; Visser TJ
[Ad] Endereço:Department of Internal Medicine and Rotterdam Thyroid Center, Erasmus University Medical Center, 3015 GE Rotterdam, The Netherlands.
[Ti] Título:Role of the Bile Acid Transporter SLC10A1 in Liver Targeting of the Lipid-Lowering Thyroid Hormone Analog Eprotirome.
[So] Source:Endocrinology;158(10):3307-3318, 2017 Oct 01.
[Is] ISSN:1945-7170
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The thyroid hormone (TH) analog eprotirome (KB2115) was developed to lower cholesterol through selective activation of the TH receptor (TR) ß1 in the liver. Interestingly, eprotirome shows low uptake in nonhepatic tissues, explaining its lipid-lowering action without adverse extrahepatic thyromimetic effects. Clinical trials have shown marked decreases in serum cholesterol levels. We explored the transport of eprotirome across the plasma membrane by members of three TH transporter families: monocarboxylate transporters MCT8 and MCT10; Na-independent organic anion transporters 1A2, 1B1, 1B3, 1C1, 2A1, and 2B1; and Na-dependent organic anion transporters SLC10A1 to SLC10A7. Cellular transport was studied in transfected COS1 cells using [14C]eprotirome and [125I]TH analogs. Of the 15 transporters tested initially, the liver-specific bile acid transporter SLC10A1 showed the highest eprotirome uptake (greater than a sevenfold induction after 60 minutes) as well as TRß1-mediated transcriptional activity. Uptake of eprotirome by SLC10A1 was Na+ dependent and saturable with a Michaelis constant of 8 µM. Eprotirome transport was inhibited by known substrates for SLC10A1 (e.g., cholate and taurocholate), and by TH analogs such as triiodothyropropionic acid and triiodothyroacetic acid. However, no significant SLC10A1-mediated transport was observed of these [125I]TH analogs. We also studied the plasma disappearance and biliary excretion of [14C]eprotirome injected in control and Slc10a1 knockout mice. Although eprotirome is also transported by mouse Slc10a1, the pharmacokinetics of eprotirome were not affected by Slc10a1 deficiency. In conclusion, we have demonstrated that the liver-specific bile acid transporter SLC10A1 effectively transports eprotirome. However, Slc10a1 does not appear to be critical for the liver targeting of this TH analog in mice. Therefore, the importance of SLC10A1 for liver uptake of eprotirome in humans remains to be elucidated.
[Mh] Termos MeSH primário: Anilidas/farmacologia
Anilidas/farmacocinética
Anticolesterolemiantes
Fígado/efeitos dos fármacos
Transportadores de Ânions Orgânicos Dependentes de Sódio/fisiologia
Simportadores/fisiologia
[Mh] Termos MeSH secundário: Animais
Transporte Biológico
Células COS
Membrana Celular/metabolismo
Cercopithecus aethiops
Seres Humanos
Fígado/metabolismo
Camundongos
Camundongos Knockout
Terapia de Alvo Molecular
Transportadores de Ácidos Monocarboxílicos/metabolismo
Transportadores de Ânions Orgânicos/metabolismo
Transportadores de Ânions Orgânicos Dependentes de Sódio/deficiência
Transportadores de Ânions Orgânicos Dependentes de Sódio/genética
RNA Mensageiro/análise
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Sódio/farmacologia
Simportadores/deficiência
Simportadores/genética
Hormônios Tireóideos/metabolismo
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3-((3,5-dibromo-4-(4-hydroxy-3-(1-methylethyl)phenoxy)phenyl)amino)-3-oxopropanoic acid); 0 (Anilides); 0 (Anticholesteremic Agents); 0 (Monocarboxylic Acid Transporters); 0 (Organic Anion Transporters); 0 (Organic Anion Transporters, Sodium-Dependent); 0 (RNA, Messenger); 0 (Symporters); 0 (Thyroid Hormones); 145420-23-1 (sodium-bile acid cotransporter); 9NEZ333N27 (Sodium)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170923
[St] Status:MEDLINE
[do] DOI:10.1210/en.2017-00433


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[PMID]:28731330
[Au] Autor:Colas C; Schlessinger A; Pajor AM
[Ad] Endereço:Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.
[Ti] Título:Mapping Functionally Important Residues in the Na /Dicarboxylate Cotransporter, NaDC1.
[So] Source:Biochemistry;56(33):4432-4441, 2017 Aug 22.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Transporters from the SLC13 family couple the transport of two to four Na ions with a di- or tricarboxylate, such as succinate or citrate. We have previously modeled mammalian members of the SLC13 family, including the Na /dicarboxylate cotransporter NaDC1 (SLC13A2), based on a structure of the bacterial homologue VcINDY in an inward-facing conformation with one sodium ion bound at the Na1 site. In the study presented here, we modeled the outward-facing conformation of rabbit and human NaDC1 (rbNaDC1 and hNaDC1, respectively) using an outward-facing model of VcINDY as a template and identified residues in or near the putative Na2 and Na3 cation binding sites. Guided by the structural models in both conformations, we performed site-directed mutagenesis in rbNaDC1 for residues proposed to be in the Na or substrate binding sites. Cysteine substitution of T474 in the predicted Na2 binding site results in an inactive protein. The M539C mutant has a low apparent affinity for both sodium and lithium cations, suggesting that M539 may form part of the putative Na3 binding site. The Y432C and T86C mutants have increased K values for succinate, supporting their proposed location in the outward-facing substrate binding site. In addition, cysteine labeling by MTSEA-biotin shows that Y432C is accessible from the outside of the cell, and the accessibility changes in the presence or absence of Na . The results of this study improve our understanding of substrate and ion recognition in the mammalian members of the SLC13 family and provide a framework for developing conformationally specific inhibitors against these transporters.
[Mh] Termos MeSH primário: Transportadores de Ácidos Dicarboxílicos/química
Lítio/química
Modelos Moleculares
Transportadores de Ânions Orgânicos Dependentes de Sódio/química
Sódio/química
Ácido Succínico/química
Simportadores/química
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Sítios de Ligação
Cátions Monovalentes/química
Cátions Monovalentes/metabolismo
Transportadores de Ácidos Dicarboxílicos/genética
Transportadores de Ácidos Dicarboxílicos/metabolismo
Células HEK293
Seres Humanos
Lítio/metabolismo
Mutação de Sentido Incorreto
Transportadores de Ânions Orgânicos Dependentes de Sódio/genética
Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo
Mapeamento de Peptídeos
Coelhos
Sódio/metabolismo
Ácido Succínico/metabolismo
Simportadores/genética
Simportadores/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cations, Monovalent); 0 (Dicarboxylic Acid Transporters); 0 (Organic Anion Transporters, Sodium-Dependent); 0 (SLC13A2 protein, human); 0 (Symporters); 9FN79X2M3F (Lithium); 9NEZ333N27 (Sodium); AB6MNQ6J6L (Succinic Acid)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170831
[Lr] Data última revisão:
170831
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170722
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00503


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[PMID]:28662289
[Au] Autor:Lin YY; Yu MW; Lin SM; Lee SD; Chen CL; Chen DS; Chen PJ
[Ad] Endereço:Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan.
[Ti] Título:Genome-wide association analysis identifies a GLUL haplotype for familial hepatitis B virus-related hepatocellular carcinoma.
[So] Source:Cancer;123(20):3966-3976, 2017 Oct 15.
[Is] ISSN:1097-0142
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: A family history of liver cancer increases the risk of developing hepatocellular carcinoma (HCC) by 2-fold to 10-fold among patients with chronic hepatitis B virus (HBV). Previous genome-wide association studies have identified many possible susceptible loci associated with sporadic HBV-related HCC. However, despite family history being a well-known risk factor for HBV-related HCC, to the authors' knowledge its genetic mechanisms and associating loci remain largely unknown or unexplored, most likely due to the relative rarity of familial HCC and the difficulty of sample collection. METHODS: The authors conducted a genome-wide association study with 139 male cases with familial HBV-related HCC and 139 non-HCC male controls with chronic HBV. The results were corroborated further with an independent cohort of 101 patients with familial HBV-related HCC and comparison with both the 1000 Genomes Project and the Taiwan Biobank. RESULTS: A total of 51 risk single-nucleotide polymorphisms (P≤1E-04) were identified in the association analyses, which included 2 clusters of associated single-nucleotide polymorphisms and haplotypes at 1q25.3 (glutamate-ammonia ligase [GLUL]/transmembrane epididymal protein 1 [TEDDM1]/long intergenic non-protein-coding RNA 272 [LINC00272]/regulator of G-protein signaling-like 1 [RGSL1]) and 17q11.2 (solute carrier family 13 member 2 [SLC13A2]/forkhead box N1 [FOXN1]). Both the GLUL and SLC13A2/FOXN1 haplotypes have large effect sizes and were found to be different from those found from genome-wide association studies of sporadic HCCs. CONCLUSIONS: To the authors' knowledge, the current study is the first genome-wide association study to identify genetic factors for familial HBV-related HCC. The results identified 2 large effect susceptible haplotypes located at GLUL and SLC13A2/FOXN1. The current study findings also suggest different genetic susceptibility between familial and sporadic HBV-related HCC. Cancer 2017;123:3966-76. © 2017 American Cancer Society.
[Mh] Termos MeSH primário: Carcinoma Hepatocelular/genética
Glutamato-Amônia Ligase/genética
Neoplasias Hepáticas/genética
[Mh] Termos MeSH secundário: Adulto
Idoso
Grupo com Ancestrais do Continente Asiático/genética
Estudos de Casos e Controles
Transportadores de Ácidos Dicarboxílicos/genética
Fatores de Transcrição Forkhead/genética
Predisposição Genética para Doença
Estudo de Associação Genômica Ampla
Genótipo
Haplótipos
Hepatite B Crônica/complicações
Seres Humanos
Masculino
Proteínas de Membrana/genética
Meia-Idade
Transportadores de Ânions Orgânicos Dependentes de Sódio/genética
Polimorfismo de Nucleotídeo Único
Proteínas/genética
RNA Longo não Codificante/genética
Simportadores/genética
Taiwan
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Dicarboxylic Acid Transporters); 0 (Forkhead Transcription Factors); 0 (Membrane Proteins); 0 (Organic Anion Transporters, Sodium-Dependent); 0 (Proteins); 0 (RGSL1 protein, human); 0 (RNA, Long Noncoding); 0 (SLC13A2 protein, human); 0 (Symporters); 0 (TEDDM1 protein, human); 0 (Whn protein); EC 6.3.1.2 (Glutamate-Ammonia Ligase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171011
[Lr] Data última revisão:
171011
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170630
[St] Status:MEDLINE
[do] DOI:10.1002/cncr.30851


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[PMID]:28644885
[Au] Autor:Zhang Y; Boxberger KH; Hagenbuch B
[Ad] Endereço:Department of Pharmacology, Toxicology and Therapeutics, the University of Kansas Medical Center, Kansas City, Kansas, United States of America.
[Ti] Título:Organic anion transporting polypeptide 1B3 can form homo- and hetero-oligomers.
[So] Source:PLoS One;12(6):e0180257, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OATP1B3 is a 12 transmembrane domain protein expressed at the basolateral membrane of human hepatocytes where it mediates the uptake of numerous drugs and endogenous compounds. Previous western blot results suggest the formation of OATP1B3 multimers. In order to better understand the function of OATP1B3 under normal physiological conditions, we investigated its oligomerization status. We transiently transfected OATP1B3 with a C-terminal His-, FLAG- or HA-tag in HEK293 cells and used co-immunoprecipitation and a Proximity Ligation Assay to detect interactions between the different constructs. All three constructs retained similar transport rates as wild-type OATP1B3. Immunofluorescence experiments indicated that in contrast to wild-type, His- and FLAG-tagged OATP1B3, where the C-terminal end is on the cytoplasmic side of the membrane, the C-terminal end of HA-tagged OATP1B3 is extracellular. After cross-linking, anti-FLAG antibodies were able to pull down FLAG-tagged OATP1B3 (positive control) and co-transfected His- or HA-tagged OATP1B3, demonstrating the formation of homo-oligomers and suggesting that the C-terminal part is not involved in oligomer formation. We confirmed co-localization of His- and FLAG-tagged OATP1B3 in transfected HEK293 cells with the Proximity Ligation Assay. Transport studies with a non-functional OATP1B3 mutant suggest that the individual subunits and not the whole oligomer are the functional units in the homo-oligomers. In addition, we also detected OATP1B3-FLAG co-localization with OATP1B1-His or NTCP-His, suggesting that OATP1B3 also hetero-oligomerizes with other transport proteins. Using the Proximity Ligation Assay with transporter specific antibodies, we demonstrate close association of OATP1B3 with NTCP in frozen human liver tissue. These findings demonstrate that OATP1B3 can form homo- and hetero-oligomers and suggest a potential co-regulation of the involved transporters.
[Mh] Termos MeSH primário: Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo
[Mh] Termos MeSH secundário: Western Blotting
Citoplasma/metabolismo
Espaço Extracelular/metabolismo
Imunofluorescência
Células HEK293
Seres Humanos
Imunoprecipitação
Mutação
Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo
Transportadores de Ânions Orgânicos Sódio-Independentes/química
Transportadores de Ânions Orgânicos Sódio-Independentes/genética
Domínios Proteicos
Multimerização Proteica
Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto
Membro 1b1 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo
Simportadores/metabolismo
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Organic Anion Transporters, Sodium-Dependent); 0 (Organic Anion Transporters, Sodium-Independent); 0 (SLCO1B1 protein, human); 0 (SLCO1B3 protein, human); 0 (Solute Carrier Organic Anion Transporter Family Member 1B3); 0 (Solute Carrier Organic Anion Transporter Family Member 1b1); 0 (Symporters); 145420-23-1 (sodium-bile acid cotransporter)
[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:170624
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0180257


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[PMID]:28498614
[Au] Autor:Slijepcevic D; Roscam Abbing RLP; Katafuchi T; Blank A; Donkers JM; van Hoppe S; de Waart DR; Tolenaars D; van der Meer JHM; Wildenberg M; Beuers U; Oude Elferink RPJ; Schinkel AH; van de Graaf SFJ
[Ad] Endereço:Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
[Ti] Título:Hepatic uptake of conjugated bile acids is mediated by both sodium taurocholate cotransporting polypeptide and organic anion transporting polypeptides and modulated by intestinal sensing of plasma bile acid levels in mice.
[So] Source:Hepatology;66(5):1631-1643, 2017 Nov.
[Is] ISSN:1527-3350
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The Na -taurocholate cotransporting polypeptide (NTCP/SLC10A1) is believed to be pivotal for hepatic uptake of conjugated bile acids. However, plasma bile acid levels are normal in a subset of NTCP knockout mice and in mice treated with myrcludex B, a specific NTCP inhibitor. Here, we elucidated which transport proteins mediate the hepatic uptake of conjugated bile acids and demonstrated intestinal sensing of elevated bile acid levels in plasma in mice. Mice or healthy volunteers were treated with myrcludex B. Hepatic bile acid uptake kinetics were determined in wild-type (WT), organic anion transporting polypeptide (OATP) knockout mice (lacking Slco1a/1b isoforms), and human OATP1B1-transgenic mice. Effects of fibroblast growth factor 19 (FGF19) on hepatic transporter mRNA levels were assessed in rat hepatoma cells and in mice by peptide injection or adeno-associated virus-mediated overexpression. NTCP inhibition using myrcludex B had only moderate effects on bile acid kinetics in WT mice, but completely inhibited active transport of conjugated bile acid species in OATP knockout mice. Cholesterol 7α-hydroxylase Cyp7a1 expression was strongly down-regulated upon prolonged inhibition of hepatic uptake of conjugated bile acids. Fgf15 (mouse counterpart of FGF19) expression was induced in hypercholanemic OATP and NTCP knockout mice, as well as in myrcludex B-treated cholestatic mice, whereas plasma FGF19 was not induced in humans treated with myrcludex B. Fgf15/FGF19 expression was induced in polarized human enterocyte-models and mouse organoids by basolateral incubation with a high concentration (1 mM) of conjugated bile acids. CONCLUSION: NTCP and OATPs contribute to hepatic uptake of conjugated bile acids in mice, whereas the predominant uptake in humans is NTCP mediated. Enterocytes sense highly elevated levels of (conjugated) bile acids in the systemic circulation to induce FGF15/19, which modulates hepatic bile acid synthesis and uptake. (Hepatology 2017;66:1631-1643).
[Mh] Termos MeSH primário: Ácidos e Sais Biliares/metabolismo
Enterócitos/fisiologia
Fatores de Crescimento de Fibroblastos/metabolismo
Fígado/metabolismo
Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo
Simportadores/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Colesterol 7-alfa-Hidroxilase/metabolismo
Regulação para Baixo
Feminino
Seres Humanos
Íleo/metabolismo
Lipopeptídeos
Masculino
Camundongos Endogâmicos C57BL
Camundongos Knockout
Isoformas de Proteínas/metabolismo
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bile Acids and Salts); 0 (Lipopeptides); 0 (Organic Anion Transporters, Sodium-Dependent); 0 (Protein Isoforms); 0 (Symporters); 0 (fibroblast growth factor 15, mouse); 0 (myrcludex-B); 145420-23-1 (sodium-bile acid cotransporter); 62031-54-3 (Fibroblast Growth Factors); EC 1.14.14.23 (Cholesterol 7-alpha-Hydroxylase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170513
[St] Status:MEDLINE
[do] DOI:10.1002/hep.29251


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[PMID]:28302211
[Au] Autor:Song YZ; Deng M
[Ad] Endereço:Department of Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou 510630, China. songyuanzong@vip.tom.com.
[Ti] Título:[Sodium taurocholate cotransporting polypeptide deficiency manifesting as cholestatic jaundice in early infancy: a complicated case study].
[So] Source:Zhongguo Dang Dai Er Ke Za Zhi;19(3):350-354, 2017 Mar.
[Is] ISSN:1008-8830
[Cp] País de publicação:China
[La] Idioma:chi
[Ab] Resumo:Sodium taurocholate cotransporting polypeptide (NTCP) deficiency is caused by SLC10A1 mutations impairing the NTCP function to uptake plasma bile salts into the hepatocyte. Thus far, patients with NTCP deficiency were rarely reported. The patient in this paper was a 5-month-19-day male infant with the complaint of jaundiced skin and sclera for 5.5 months as well as abnormal liver function revealed over 4 months. His jaundice was noticed on the second day after birth, and remained visible till his age of 1 month and 13 days, when a liver function test unveiled markedly elevated total, direct and indirect bilirubin as well as total bile acids (TBA). Cholestatic liver disease was thus diagnosed. Due to unsatisfactory response to medical treatment, the patient underwent exploratory laparotomy, cholecystostomy and cholangiography when aged 2 months. This revealed inspissated bile but unobstructed bile ducts. Thereafter, his jaundice subsided, but the aminotransferases and TBA levels gradually rose. Of note, his mother also had mildly elevated plasma TBA. Since the etiology was unclear, no specific medication was introduced. The infant has been followed up over 2 years. The aminotransferases recovered gradually, but TBA levels fluctuated within 23.3-277.7 µmol/L (reference range: 0-10 µmol/L). On SLC10A1 genetic analysis at 2 years and 9 months, both the infant and his mother proved to be homozygous for a pathogenic variant c.800C>T(p.S267F), and NTCP deficiency was thus definitely diagnosed. The findings suggest that, although only mildly increased plasma TBA is presented in adults with NTCP deficiency, pediatric patients with this disorder exhibit persistent and remarkable hypercholanemia, and some patients might manifest as cholestatic jaundice in early infancy.
[Mh] Termos MeSH primário: Icterícia Obstrutiva/etiologia
Transportadores de Ânions Orgânicos Dependentes de Sódio/deficiência
Simportadores/deficiência
[Mh] Termos MeSH secundário: Seres Humanos
Lactente
Masculino
Transportadores de Ânions Orgânicos Dependentes de Sódio/sangue
Transportadores de Ânions Orgânicos Dependentes de Sódio/genética
Simportadores/sangue
Simportadores/genética
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Organic Anion Transporters, Sodium-Dependent); 0 (Symporters); 145420-23-1 (sodium-bile acid cotransporter)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170801
[Lr] Data última revisão:
170801
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170318
[St] Status:MEDLINE


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[PMID]:28262508
[Au] Autor:Qu XY; Tao LN; Zhang SX; Sun JM; Niu JQ; Ding YH; Song YQ
[Ad] Endereço:Depatment of Pharmacy, the First Hospital of Jilin University, Changchun, China.
[Ti] Título:The role of Ntcp, Oatp2, Bsep and Mrp2 in liver injury induced by Dioscorea bulbifera L. and Diosbulbin B in mice.
[So] Source:Environ Toxicol Pharmacol;51:16-22, 2017 Apr.
[Is] ISSN:1872-7077
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Dioscorea bulbifera L. (DB) is a traditional Chinese herb used in thyroid disease and cancer. However, the clinical use of DB remains a challenge due to its hepatotoxicity, which is caused, in part, by the presence of Diosbulbin B (DIOB), a toxin commonly found in DB extracts. As abnormal expression of hepatobiliary transporters plays an important role in drug-induced liver injury, we assessed the hepatotoxicity induced by DB and DIOB, and explored their impacts on hepatobiliary transporter expression levels. Following liquid chromatography-tandem mass analysis of the DIOB content of DB extract, male ICR mice were randomly orally administered DB or DIOB for 14days. Liver injury was assessed by histopathological and biochemical analysis of liver fuction. The levels of transporter protein and mRNA were determined by western blotting and real-time PCR. Liver function and histopathological analysis indicated that both DB and DIOB could induce liver injury in mice, and that DIOB might be the primary toxic compound in DB. Moreover, down-regulation of Mrp2 blocked the excretion of bilirubin, glutathione disulfide, and bile acids, leading to the accumulation of toxic substrates in the liver and a redox imbalance. We identified down-regulated expression of Mrp2 as potential factors linked to increased serum bilirubin levels and decreased levels of glutathione in the liver and increased liver injury severity. In summary, our study indicates that down-regulation of Mrp2 represents the primary mechanism of DB- and DIOB-induced hepatotoxicity, and provides insight into novel therapies that could be used to prevent DB- and DIOB-mediated liver injury.
[Mh] Termos MeSH primário: Transportadores de Cassetes de Ligação de ATP/metabolismo
Doença Hepática Induzida por Substâncias e Drogas/metabolismo
Dioscorea/química
Medicamentos de Ervas Chinesas/toxicidade
Compostos Heterocíclicos de 4 ou mais Anéis/toxicidade
Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo
Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo
Proteínas de Transporte de Cátions Orgânicos/metabolismo
Simportadores/metabolismo
[Mh] Termos MeSH secundário: Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP
Transportadores de Cassetes de Ligação de ATP/genética
Animais
Doença Hepática Induzida por Substâncias e Drogas/etiologia
Doença Hepática Induzida por Substâncias e Drogas/patologia
Medicamentos de Ervas Chinesas/isolamento & purificação
Expressão Gênica/efeitos dos fármacos
Compostos Heterocíclicos de 4 ou mais Anéis/isolamento & purificação
Peroxidação de Lipídeos/efeitos dos fármacos
Fígado/efeitos dos fármacos
Fígado/metabolismo
Fígado/patologia
Masculino
Camundongos Endogâmicos ICR
Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética
Transportadores de Ânions Orgânicos Dependentes de Sódio/genética
Proteínas de Transporte de Cátions Orgânicos/genética
Simportadores/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ATP Binding Cassette Subfamily B Member 11); 0 (Abcb11 protein, mouse); 0 (Drugs, Chinese Herbal); 0 (Heterocyclic Compounds, 4 or More Rings); 0 (Multidrug Resistance-Associated Proteins); 0 (Oatp2 protein, mouse); 0 (Organic Anion Transporters, Sodium-Dependent); 0 (Organic Cation Transport Proteins); 0 (Symporters); 145420-23-1 (sodium-bile acid cotransporter); 20086-06-0 (diosbulbin B); 4AF605U6JN (multidrug resistance-associated protein 2)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170307
[St] Status:MEDLINE


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[PMID]:28258579
[Au] Autor:Huang B; Wang H; Yang B
[Ad] Endereço:Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China.
[Ti] Título:Water Transport Mediated by Other Membrane Proteins.
[So] Source:Adv Exp Med Biol;969:251-261, 2017.
[Is] ISSN:0065-2598
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Water transport through membrane is so intricate that there are still some debates. (Aquaporins) AQPs are entirely accepted to allow water transmembrane movement depending on osmotic gradient. Cotransporters and uniporters , however, are also concerned in water homeotatsis. Urea transporter B (UT-B) has a single-channel water permeability that is similar to AQP1. Cystic fibrosis transmembrane conductance regulator (CFTR ) was initially thought as a water channel but now not believed to transport water directly. By cotranporters, water is transported by water osmosis coupling with substrates, which explains how water is transported across the isolated small intestine. This chapter provides information about water transport mediated by other membrane proteins except AQPs .
[Mh] Termos MeSH primário: Células Eucarióticas/metabolismo
Transportador 1 de Aminoácido Excitatório/metabolismo
Transportadores de Ácidos Monocarboxílicos/metabolismo
Simportadores/metabolismo
Água/metabolismo
[Mh] Termos MeSH secundário: Animais
Transporte Biológico
Regulador de Condutância Transmembrana em Fibrose Cística/genética
Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo
Transportadores de Ácidos Dicarboxílicos/genética
Transportadores de Ácidos Dicarboxílicos/metabolismo
Células Eucarióticas/citologia
Transportador 1 de Aminoácido Excitatório/genética
Regulação da Expressão Gênica
Seres Humanos
Proteínas de Membrana Transportadoras/genética
Proteínas de Membrana Transportadoras/metabolismo
Transportadores de Ácidos Monocarboxílicos/genética
Transportadores de Ânions Orgânicos Dependentes de Sódio/genética
Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo
Concentração Osmolar
Transportador 1 de Glucose-Sódio/genética
Transportador 1 de Glucose-Sódio/metabolismo
Membro 2 da Família 12 de Carreador de Soluto/genética
Membro 2 da Família 12 de Carreador de Soluto/metabolismo
Simportadores/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (CFTR protein, human); 0 (Dicarboxylic Acid Transporters); 0 (Excitatory Amino Acid Transporter 1); 0 (Membrane Transport Proteins); 0 (Monocarboxylic Acid Transporters); 0 (Organic Anion Transporters, Sodium-Dependent); 0 (SLC12A7 protein, human); 0 (SLC13A2 protein, human); 0 (SLC1A3 protein, human); 0 (SLC5A1 protein, human); 0 (Sodium-Glucose Transporter 1); 0 (Solute Carrier Family 12, Member 2); 0 (Symporters); 0 (monocarboxylate transport protein 1); 0 (urea transporter); 059QF0KO0R (Water); 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170907
[Lr] Data última revisão:
170907
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170305
[St] Status:MEDLINE
[do] DOI:10.1007/978-94-024-1057-0_17


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[PMID]:28249272
[Au] Autor:Vaz FM; Huidekoper HH; Paulusma CC
[Ad] Endereço:Laboratory Genetic Metabolic Disease, Academic Medical Center, Amsterdam, The Netherlands.
[Ti] Título:Extended Abstract: Deficiency of Sodium Taurocholate Cotransporting Polypeptide (SLC10A1): A New Inborn Error of Metabolism with an Attenuated Phenotype.
[So] Source:Dig Dis;35(3):259-260, 2017.
[Is] ISSN:1421-9875
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:We present the first patient with a defect in the Na+-taurocholate cotransporting polypeptide SLC10A1 (NTCP), which plays a key role in the enterohepatic circulation of bile salts. The clinical presentation of the child was mild and the child showed no signs of liver dysfunction or pruritus despite extremely elevated plasma bile salt levels (>100-fold upper-limit of normal). A homozygous point mutation was found in the SLC10A1 gene (resulting in amino acid change R252H) and functional studies confirmed the pathogenicity of the mutation. This confirms the role of NTCP as the major transporter of conjugated bile salts into the liver as part of the enterohepatic circulation and shows that other transporters partly can take over its function, resulting in a relatively mild phenotype. This work was published previously in [Vaz et al.: Hepatology 2015;61:260-267] and supplemented with some follow-up information of the patient.
[Mh] Termos MeSH primário: Erros Inatos do Metabolismo/metabolismo
Erros Inatos do Metabolismo/patologia
Transportadores de Ânions Orgânicos Dependentes de Sódio/deficiência
Simportadores/deficiência
[Mh] Termos MeSH secundário: Ácido Quenodesoxicólico/metabolismo
Pré-Escolar
Feminino
Seguimentos
Seres Humanos
Erros Inatos do Metabolismo/diagnóstico
Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo
Fenótipo
Simportadores/metabolismo
Fatores de Tempo
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Organic Anion Transporters, Sodium-Dependent); 0 (Symporters); 0GEI24LG0J (Chenodeoxycholic Acid); 145420-23-1 (sodium-bile acid cotransporter)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170501
[Lr] Data última revisão:
170501
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170302
[St] Status:MEDLINE
[do] DOI:10.1159/000450984



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