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https://www.readbyqxmd.com/read/29658451/-clinical-and-genetic-analysis-of-a-pediatric-patient-with-sodium-taurocholate-cotransporting-polypeptide-deficiency
#1
Hua Li, Jian-Wu Qiu, Gui-Zhi Lin, Mei Deng, Wei-Xia Lin, Ying Cheng, Yuan-Zong Song
Sodium taurocholate cotransporting polypeptide (NTCP) deficiency is an inborn error of bile acid metabolism caused by mutations of SLC10A1 gene. This paper reports the clinical and genetic features of a patient with this disease. A 3.3-month-old male infant was referred to the hospital with the complaint of jaundiced skin and sclera over 3 months. Physical examination revealed moderate jaundice of the skin and sclera. The liver was palpable 3.5 cm below the right subcostal margin with a medium texture. Serum biochemistry analysis revealed markedly elevated bilirubin (predominantly direct bilirubin) and total bile acids (TBA), as well as decreased 25-OH-VitD level...
April 2018: Zhongguo Dang Dai Er Ke za Zhi, Chinese Journal of Contemporary Pediatrics
https://www.readbyqxmd.com/read/29610217/sequence-based-analysis-of-lipid-related-metabolites-in-a-multiethnic-study
#2
Elena V Feofanova, Bing Yu, Ginger A Metcalf, Xiaoming Liu, Donna Muzny, Jennifer E Below, Lynne E Wagenknecht, Richard A Gibbs, Alanna C Morrison, Eric Boerwinkle
Small molecule lipid-related metabolites are important components of fatty acid and steroid metabolism, two important contributors to human health. This study investigated the extent to which rare and common genetic variants spanning the human genome influence the lipid-related metabolome. Sequence data from 1,552 European-Americans (EA) and 1,872 African-Americans (AA) were analyzed to examine the impact of common and rare variants on the levels of 102 circulating lipid-related metabolites measured by a combination of chromatography and mass spectroscopy...
April 2, 2018: Genetics
https://www.readbyqxmd.com/read/29440451/establishing-transcriptional-signatures-to-differentiate-pxr-car-and-ahr-mediated-regulation-of-drug-metabolism-and-transport-genes-in-cryopreserved-human-hepatocytes
#3
Jamie E Moscovitz, Amit S Kalgutkar, Kelly Nulick, Nathaniel Johnson, Zhiwu Lin, Theunis C Goosen, Yan Weng
The potential for drug-drug interactions (DDIs) arising from transcriptional regulation of drug-disposition genes via activation of nuclear receptors (NRs), such as pregnane X receptor (PXR), constitutive androstane receptor (CAR), and aryl hydrocarbon receptor (AhR), remains largely unexplored, as highlighted in a recent guidance document from the European Medicines Agency. The goal of this research was to establish PXR-/CAR-/AhR-specific drug-metabolizing enzyme (DME) and transporter gene expression signatures in sandwich-cultured cryopreserved human hepatocytes using selective activators of PXR (rifampin), CAR (CITCO), and AhR (omeprazole)...
May 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29439128/comparison-of-proteomic-quantification-approaches-for-hepatic-drug-transporters-multiplexed-global-quantitation-correlates-with-targeted-proteomic-quantitation
#4
Anna Vildhede, Chuong Nguyen, Brian K Erickson, Ryan C Kunz, Richard Jones, Emi Kimoto, Francis Bourbonais, A David Rodrigues, Manthena V S Varma
Targeted protein quantification using liquid chromatography-tandem mass spectrometry with stable isotope-labeled standards is recognized as the gold standard of practice for protein quantification. Such assays, however, can only cover a limited number of proteins, and developing targeted methods for larger numbers of proteins requires substantial investment. Alternatively, large-scale global proteomic experiments along with computational methods such as the "total protein approach" (TPA) have the potential to provide extensive protein quantification...
May 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29290974/sodium-taurocholate-cotransporting-polypeptide-ntcp-deficiency-identification-of-a-novel-slc10a1-mutation-in-two-unrelated-infants-presenting-with-neonatal-indirect-hyperbilirubinemia-and-remarkable-hypercholanemia
#5
Jian-Wu Qiu, Mei Deng, Ying Cheng, Raza-Muhammad Atif, Wei-Xia Lin, Li Guo, Hua Li, Yuan-Zong Song
Sodium taurocholate cotransporting polypeptide (NTCP) is encoded by the gene SLC10A1 and expressed in the basolateral membrane of the hepatocyte, functioning to uptake bile acids from plasma. Although SLC10A1 has been cloned and NTCP function studied intensively for years, clinical description of NTCP deficiency remains rather limited. This study reported the genotypic and phenotypic features of two neonatal patients with NTCP deficiency. They both presented with neonatal indirect hyperbilirubinemia and remarkable hypercholanemia, and harbored the SLC10A1 variants c...
December 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/29285260/genetic-variations-of-ntcp-are-associated-with-susceptibility-to-hbv-infection-and-related-hepatocellular-carcinoma
#6
Peng Wang, Ruidong Mo, Rongtao Lai, Yumin Xu, Jie Lu, Gangde Zhao, Yuhan Liu, Zhujun Cao, Xiaolin Wang, Ziqiang Li, Lanyi Lin, Huijuan Zhou, Wei Cai, Hui Wang, Shisan Bao, Xiaogang Xiang, Qing Xie
Sodium taurocholate cotransporting polypeptide (NTCP), encoded by gene SLC10A1, is a receptor for hepatitis B virus (HBV). The aim of the current study was to investigate the role of NTCP polymorphisms in HBV susceptibility, cirrhosis and hepatocarcinogenesis. A total 1221 cases [including 866 chronic hepatitis B (CHB), 238 liver cirrhosis (LC), 117 hepatocellular carcinoma (HCC) patients] and 1232 healthy controls (HCs) were recruited, and 6 single nucleotide polymorphisms (SNPs) were genotyped. Meta-analysis was executed among 14591 CHBs and 12396 HCs to determine the association between NTCP polymorphisms and HBV infection, cirrhosis or hepatocarcinogenesis...
December 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/29222397/indoxyl-sulfate-upregulates-liver-p-glycoprotein-expression-and-activity-through-aryl-hydrocarbon-receptor-signaling
#7
Tacy Santana Machado, Stéphane Poitevin, Pascale Paul, Nathalie McKay, Noémie Jourde-Chiche, Tristan Legris, Annick Mouly-Bandini, Françoise Dignat-George, Philippe Brunet, Rosalinde Masereeuw, Stéphane Burtey, Claire Cerini
In patients with CKD, not only renal but also, nonrenal clearance of drugs is altered. Uremic toxins could modify the expression and/or activity of drug transporters in the liver. We tested whether the uremic toxin indoxyl sulfate (IS), an endogenous ligand of the transcription factor aryl hydrocarbon receptor, could change the expression of the following liver transporters involved in drug clearance: SLC10A1 , SLC22A1 , SLC22A7 , SLC47A1 , SLCO1B1 , SLCO1B3 , SLCO2B1 , ABCB1 , ABCB11 , ABCC2 , ABCC3 , ABCC4 , ABCC6 , and ABCG2 We showed that IS increases the expression and activity of the efflux transporter P-glycoprotein (P-gp) encoded by ABCB1 in human hepatoma cells (HepG2) without modifying the expression of the other transporters...
March 2018: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/29212823/quantitative-expression-of-hepatobiliary-transporters-and-functional-uptake-of-substrates-in-hepatic-two-dimensional-sandwich-cultures-a-comparative-evaluation-of-upcyte-and-primary-human-hepatocytes
#8
Michelle Schaefer, Gaku Morinaga, Akiko Matsui, Gerhard Schänzle, Daniel Bischoff, Roderich D Süssmuth
Deficient functional expression of drug transporters incapacitates most hepatic cell lines as a reliable tool for evaluating transporter-mediated drug-drug interactions. Recently, genetically modified cells (referred to as upcyte hepatocytes) have emerged as an expandable, noncancerous source of human hepatic cells. Herein, we quantified mRNA and protein levels of key hepatobiliary transporters and we assessed associated uptake activity in short- and long-term cultures of upcyte human hepatocytes (UHH) in comparison to cryopreserved primary human hepatocytes (cPHH)...
February 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29127322/reduced-hepatitis-b-and-d-viral-entry-using-clinically-applied-drugs-as-novel-inhibitors-of-the-bile-acid-transporter-ntcp
#9
Joanne M Donkers, Benno Zehnder, Gerard J P van Westen, Mark J Kwakkenbos, Adriaan P IJzerman, Ronald P J Oude Elferink, Ulrich Beuers, Stephan Urban, Stan F J van de Graaf
The sodium taurocholate co-transporting polypeptide (NTCP, SLC10A1) is the main hepatic transporter of conjugated bile acids, and the entry receptor for hepatitis B virus (HBV) and hepatitis delta virus (HDV). Myrcludex B, a synthetic peptide mimicking the NTCP-binding domain of HBV, effectively blocks HBV and HDV infection. In addition, Myrcludex B inhibits NTCP-mediated bile acid uptake, suggesting that also other NTCP inhibitors could potentially be a novel treatment of HBV/HDV infection. This study aims to identify clinically-applied compounds intervening with NTCP-mediated bile acid transport and HBV/HDV infection...
November 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29024779/kinetic-characterization-of-bile-salt-transport-by-human-ntcp-slc10a1
#10
Márton Jani, Erzsébet Beéry, Teresa Heslop, Beáta Tóth, Bhavana Jagota, Emese Kis, B Kevin Park, Peter Krajcsi, Richard J Weaver
The transport of bile acids facilitated by NTCP is an important factor in establishing bile flow. In this study, we examine the kinetics associated with human NTCP-dependent transport of two quantitatively important bile acids comprising the human bile acid pool, chenodeoxycholic acid and glycine-chenodeoxycholate, and secondary bile salt, 3-sulfo-glycolithocholate of potential toxicological significance. The study employed human NTCP overexpressing Chinese Hamster Ovary cells and results compared with taurocholate, a prototypical bile salt commonly used in transporter studies...
October 9, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/28938430/role-of-the-bile-acid-transporter-slc10a1-in-liver-targeting-of-the-lipid-lowering-thyroid-hormone-analog-eprotirome
#11
Simone Kersseboom, Anja L M van Gucht, Alies van Mullem, Giulia Brigante, Stefania Farina, Bo Carlsson, Joanne M Donkers, Stan F J van de Graaf, Robin P Peeters, Theo J Visser
The thyroid hormone (TH) analog eprotirome (KB2115) was developed to lower cholesterol through selective activation of the TH receptor (TR) β1 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...
October 1, 2017: Endocrinology
https://www.readbyqxmd.com/read/28835676/homozygous-p-ser267phe-in-slc10a1-is-associated-with-a-new-type-of-hypercholanemia-and-implications-for-personalized-medicine
#12
Ruihong Liu, Chuming Chen, Xuefeng Xia, Qijun Liao, Qiong Wang, Paul J Newcombe, Shuhua Xu, Minghui Chen, Yue Ding, Xiaoying Li, Zhihong Liao, Fucheng Li, Minlian Du, Huaiqiu Huang, Ruimin Dong, Weiping Deng, Ye Wang, Binghui Zeng, Qihao Pan, Danhua Jiang, Hao Zeng, Pak Sham, Yingnan Cao, Patrick H Maxwell, Zhi-Liang Gao, Liang Peng, Yiming Wang
SLC10A1 codes for the sodium-taurocholate cotransporting polypeptide (NTCP), which is a hepatocellular transporter for bile acids (BAs) and the receptor for hepatitis B and D viruses. NTCP is also a target of multiple drugs. We aimed to evaluate the medical consequences of the loss of function mutation p.Ser267Phe in SLC10A1. We identified eight individuals with homozygous p.Ser267Phe mutation in SLC10A1 and followed up for 8-90 months. We compared their total serum BAs and 6 species of BAs with 170 wild-type and 107 heterozygous healthy individuals...
August 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28794147/erratum-the-rs2296651-s267f-variant-on-ntcp-slc10a1-is-inversely-associated-with-chronic-hepatitis-b-and-progression-to-cirrhosis-and-hepatocellular-carcinoma-in-patients-with-chronic-hepatitis-b
#13
https://www.readbyqxmd.com/read/28725001/2-3-7-8-tetrachlorodibenzo-p-dioxin-tcdd-elicited-effects-on-bile-acid-homeostasis-alterations-in-biosynthesis-enterohepatic-circulation-and-microbial-metabolism
#14
Kelly A Fader, Rance Nault, Chen Zhang, Kazuyoshi Kumagai, Jack R Harkema, Timothy R Zacharewski
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant which elicits hepatotoxicity through activation of the aryl hydrocarbon receptor (AhR). Male C57BL/6 mice orally gavaged with TCDD (0.01-30 µg/kg) every 4 days for 28 days exhibited bile duct proliferation and pericholangitis. Mass spectrometry analysis detected a 4.6-fold increase in total hepatic bile acid levels, despite the coordinated repression of genes involved in cholesterol and primary bile acid biosynthesis including Cyp7a1...
July 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28543042/the-ntcp-inhibitor-myrcludex-b-effects-on-bile-acid-disposition-and-tenofovir-pharmacokinetics
#15
A Blank, A Eidam, M Haag, N Hohmann, J Burhenne, M Schwab, Sfj van de Graaf, M R Meyer, H H Maurer, K Meier, J Weiss, T Bruckner, A Alexandrov, S Urban, G Mikus, W E Haefeli
Myrcludex B acts as a hepatitis B and D virus entry inhibitor blocking the sodium taurocholate cotransporting polypeptide (SLC10A1). We investigated the effects of myrcludex B on plasma bile acid disposition, tenofovir pharmacokinetics, and perpetrator characteristics on cytochrome P450 (CYP) 3A. Twelve healthy volunteers received 300 mg tenofovir disoproxil fumarate orally and 10 mg subcutaneous myrcludex B. Myrcludex B increased total plasma bile acid exposure 19.2-fold without signs of cholestasis. The rise in conjugated bile acids was up to 124-fold (taurocholic acid)...
February 2018: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28498614/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
#16
Davor Slijepcevic, Reinout L P Roscam Abbing, Takeshi Katafuchi, Antje Blank, Joanne M Donkers, Stéphanie van Hoppe, Dirk R de Waart, Dagmar Tolenaars, Jonathan H M van der Meer, Manon Wildenberg, Ulrich Beuers, Ronald P J Oude Elferink, Alfred H Schinkel, Stan F J van de Graaf
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...
November 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28429786/comprehensive-assessment-showed-no-associations-of-variants-at-the-slc10a1-locus-with-susceptibility-to-persistent-hbv-infection-among-southern-chinese
#17
Ying Zhang, Yuanfeng Li, Miantao Wu, Pengbo Cao, Xiaomin Liu, Qian Ren, Yun Zhai, Bobo Xie, Yanling Hu, Zhibin Hu, Jinxin Bei, Jie Ping, Xinyi Liu, Yinghua Yu, Bingqian Guo, Hui Lu, Guanjun Liu, Haitao Zhang, Ying Cui, Zengnan Mo, Hongbing Shen, Yi-Xin Zeng, Fuchu He, Hongxing Zhang, Gangqiao Zhou
The sodium taurocholate cotransporting polypeptide (NTCP) encoded by SLC10A1 was recently demonstrated to be a functional receptor for hepatitis B virus (HBV). The role of SLC10A1 polymorphisms, particularly the Ser267Phe variant (rs2296651) in exon 4, has been frequently investigated in regard to risk of persistent HBV infection. However, these investigations have generated conflicting results. To examine whether common genetic variation at the SLC10A1 locus is associated with risk of persistent HBV infection, haplotype-tagging and imputed single nucleotide polymorphisms (SNPs) were assessed in two case-control sample sets, totally including 2,550 cases (persistently HBV infected subjects, PIs) and 2,124 controls (spontaneously recovered subjects, SRs) of Southern Chinese ancestry...
April 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28302211/-sodium-taurocholate-cotransporting-polypeptide-deficiency-manifesting-as-cholestatic-jaundice-in-early-infancy-a-complicated-case-study
#18
Yuan-Zong Song, Mei Deng
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)...
March 2017: Zhongguo Dang Dai Er Ke za Zhi, Chinese Journal of Contemporary Pediatrics
https://www.readbyqxmd.com/read/28249272/extended-abstract-deficiency-of-sodium-taurocholate-cotransporting-polypeptide-slc10a1-a-new-inborn-error-of-metabolism-with-an-attenuated-phenotype
#19
Frédéric M Vaz, Hidde H Huidekoper, Coen C Paulusma
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...
2017: Digestive Diseases
https://www.readbyqxmd.com/read/28125961/lack-of-ser267phe-variant-of-sodium-taurocholate-cotransporting-polypeptide-among-moroccans-regardless-of-hepatitis-b-virus-infection-status
#20
Sayeh Ezzikouri, Hajar Chihab, Abdellah Elhabazi, Lahcen Wakrim, Soumaya Benjelloun
BACKGROUND: The sodium taurocholate co-transporting polypeptide, encoded by SLC10A1, was identified as a functional receptor for hepatitis B virus (HBV). The objective of this study was to determine if there was an association of the Ser267Phe variant (rs2296651) with HBV infection status in Moroccan patients. METHODS: Using a TaqMan 5' allelic discrimination assay, the Ser267Phe variant was genotyped in 286 chronic hepatitis B patients, 135 individuals with spontaneous clearance from HBV infection and 109 healthy controls negative for hepatitis B serological markers...
January 26, 2017: BMC Infectious Diseases
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