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Na + /taurocholate cotransporting polypeptide

Dongke Yu, Han Zhang, Daniel A Lionarons, James L Boyer, Shi-Ying Cai
The Na(+)-dependent taurocholate co-transporting polypeptide (NTCP/SLC10A1) is a hepatocyte specific solute carrier, which plays an important role in maintaining bile salt homeostasis in mammals. The absence of an hepatic Na(+)-dependent bile salt transport system in marine skate and rainbow trout raises a question regarding the function of the Slc10a1 gene in these species. Here we have characterized the Slc10a1 gene in the marine skate, Leucoraja erinacea. The transcript of skate Slc10a1 (skSlc10a1) encodes 319 amino acids and shares 46% identity to human NTCP (hNTCP) with similar topology to mammalian NTCP...
January 11, 2017: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
Bingli Liu, Yiming Li, Hong Ji, Hongwei Lu, Hua Li, Yakun Shi
To investigate the protective effect of glutamine (Gln) against obstructive cholestasis in association with farnesoid X receptor (FXR) activation, an obstructive cholestasis model was established in male Sprague-Dawley rats by bile duct ligation (BDL). Serum biomarkers and hematoxylin plus eosin staining were used to identify the degree of hepatic injury in the rats with obstructive cholestasis after Gln treatment. Immunohistochemistry, real-time PCR, Western blot, cultured primary rat hepatocytes with FXR knockdown, and dual-luciferase reporter assay were performed to elucidate the mechanisms underlying Gln hepatoprotection...
October 5, 2016: Canadian Journal of Physiology and Pharmacology
Wen Zhao, Jeremiah D Zitzow, Yi Weaver, David J Ehresman, Shu-Ching Chang, John L Butenhoff, Bruno Hagenbuch
Perfluoroalkyl sulfonates (PFSAs) such as perfluorohexane sulfonate (PFHxS) and perfluorooctane sulfonate (PFOS) have very long serum elimination half-lives in humans, and preferentially distribute to serum and liver. The enterohepatic circulation of PFHxS and PFOS likely contributes to their extended elimination half-lives. We previously demonstrated that perfluorobutane sulfonate (PFBS), PFHxS, and PFOS are transported into hepatocytes both in a sodium-dependent and a sodium-independent manner. We identified Na(+)/taurocholate cotransporting polypeptide (NTCP) as the responsible sodium-dependent transporter...
December 24, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
Kimberly Lapham, Jonathan Novak, Lisa D Marroquin, Rachel Swiss, Shuzhen Qin, Christopher J Strock, Renato Scialis, Michael D Aleo, Thomas Schroeter, Heather Eng, A David Rodrigues, Amit S Kalgutkar
Conjugated hyperbilirubinemia accompanied by cholestasis is a frequent side effect during chronic treatment with the antimicrobial agent fusidic acid. Previous studies from our laboratory, addressing mechanisms of musculoskeletal toxicity arising from coadministration of fusidic acid with statins, demonstrated the ability of fusidic acid to potently inhibit human organic anion transporting polypeptides OATP1B1 (IC50 = 1.6 μM) and OATP1B3 (IC50 = 2.5 μM), which are responsible for the uptake-limited clearance of statins as well as bilirubin glucuronide conjugates...
October 4, 2016: Chemical Research in Toxicology
Annika Sommerfeld, Patrick G K Mayer, Miriam Cantore, Dieter Häussinger
No abstract text is available yet for this article.
July 22, 2016: Journal of Biological Chemistry
Pawel E Ferdek, Monika A Jakubowska, Julia V Gerasimenko, Oleg V Gerasimenko, Ole H Petersen
KEY POINTS: Acute biliary pancreatitis is a sudden and severe condition initiated by bile reflux into the pancreas. Bile acids are known to induce Ca(2+) signals and necrosis in isolated pancreatic acinar cells but the effects of bile acids on stellate cells are unexplored. Here we show that cholate and taurocholate elicit more dramatic Ca(2+) signals and necrosis in stellate cells compared to the adjacent acinar cells in pancreatic lobules; whereas taurolithocholic acid 3-sulfate primarily affects acinar cells...
November 1, 2016: Journal of Physiology
Zhi-Tao Wu, Dan Yao, Shu-Yi Ji, Xuan Ni, Yi-Meng Gao, Li-Jian Hui, Guo-Yu Pan
BACKGROUND/AIMS: To develop a suitable hepatocyte-like cell model that could be a substitute for primary hepatocytes with essential transporter expression and functions. Induced hepatocyte-like (iHep) cells directly reprogrammed from mice fibroblast cells were fully characterized. METHODS: Naïve iHep cells were transfected with nuclear hepatocyte factor 4 alpha (Hnf4α) and treated with selected small molecules. Sandwich cultured configuration was applied. The mRNA and protein expression of transporters were determined by Real Time PCR and confocal...
2016: Cellular Physiology and Biochemistry
Zainab M Mahdi, Uta Synal-Hermanns, Aylin Yoker, Kaspar P Locher, Bruno Stieger
Drug-induced liver injury is an important clinical entity resulting in a considerable number of hospitalizations. While drug-induced cholestasis due to the inhibition of the bile salt export pump (BSEP) is well investigated, only limited information on the interaction of drugs with multidrug resistance protein 3 (MDR3) exists and its role in the pathogenesis of drug-induced cholestasis is poorly understood. Therefore, we aimed to study the interaction of drugs with MDR3 and the effect of drugs on canalicular lipid secretion in a newly established polarized cell line system that serves as a model of canalicular lipid secretion...
July 2016: Molecular Pharmacology
Xin Cheng, Weiwei Guan, Shuo Sun, Baosheng Li, Haijun Li, Fubiao Kang, Jiwen Kang, Dongliang Yang, Michael Nassal, Dianxing Sun
Hepatitis B virus (HBV) causes acute and chronic hepatitis B (CHB). Due to its error-prone replication via reverse transcription, HBV can rapidly evolve variants that escape vaccination and/or become resistant to CHB treatment with nucleoside/nucleotide analogs (NAs). This is particularly problematic for the first generation NAs lamivudine and adefovir. Though now superseded by more potent NAs, both are still widely used. Furthermore, resistance against the older NAs can contribute to cross-resistance against more advanced NAs...
2015: PloS One
Rebecca A Haeusler, Stefania Camastra, Monica Nannipieri, Brenno Astiarraga, Jose Castro-Perez, Dan Xie, Liangsu Wang, Manu Chakravarthy, Ele Ferrannini
CONTEXT: Alterations in bile acid (BA) synthesis and transport have the potential to affect multiple metabolic pathways in the pathophysiology of obesity. OBJECTIVE: The objective of the study was to investigate the effects of obesity on serum fluctuations of BAs and markers of BA synthesis. DESIGN: We measured BA fluctuations in 11 nonobese and 32 obese subjects and BA transporter expression in liver specimens from 42 individuals and specimens of duodenum, jejunum, ileum, colon, and pancreas from nine individuals...
May 2016: Journal of Clinical Endocrinology and Metabolism
Daiki Nakamori, Kazuo Takayama, Yasuhito Nagamoto, Seiji Mitani, Fuminori Sakurai, Masashi Tachibana, Hiroyuki Mizuguchi
Hepatocyte-like cells differentiated from human iPS cells (human iPS-HLCs) are expected to be utilized in drug development and research. However, recent hepatic characterization of human iPS-HLCs showed that these cells resemble fetal hepatocytes rather than adult hepatocytes. Therefore, in this study, we aimed to develop a method to enhance the hepatic function of human iPS-HLCs. Because the gene expression levels of the hepatic transcription factors (activating transcription factor 5 (ATF5), CCAAT/enhancer-binding protein alpha (c/EBPα), and prospero homeobox protein 1 (PROX1)) in adult liver were significantly higher than those in human iPS-HLCs and fetal liver, we expected that the hepatic functions of human iPS-HLCs could be enhanced by adenovirus (Ad) vector-mediated ATF5, c/EBPα, and PROX1 transduction...
January 15, 2016: Biochemical and Biophysical Research Communications
Xintao Wang, Pijun Wang, Wenjun Wang, John W Murray, Allan W Wolkoff
Na(+)-taurocholate cotransporting polypeptide (ntcp) mediates bile acid transport, also serving as the hepatitis B virus receptor. It traffics in vesicles along microtubules, requiring activity of protein kinase C (PKC)ζ for motility. We have now found that the epidermal growth factor receptor (EGFR) is the target of PKCζ activity and that EGFR and ntcp colocalize in vesicles. ntcp-containing vesicles that are not associated with EGFR have reduced microtubule-based motility, consistent with intracellular accumulation and reduced surface expression of ntcp in cells following EGFR knockdown...
March 2016: Traffic
Zahra Farahnak, Isabelle Côté, Emilienne T Ngo Sock, Jean-Marc Lavoie
BACKGROUND: The purpose of the study was to evaluate the effects of high dietary cholesterol in ovariectomized (Ovx) rats on several key markers of hepatic cholesterol and bile acid metabolism. METHOD: Ovx and sham operated (Sham) rats were given either a standard diet (SD), a SD diet supplemented with 0.25% cholesterol (SD + Chol), or a high fat diet supplemented with 0.25% cholesterol (HF + Chol) for 5 weeks. RESULTS: Ovx was associated with higher (P < 0...
2015: Lipids in Health and Disease
Manabu Kaneko, Koichi Watashi, Shinji Kamisuki, Hiroki Matsunaga, Masashi Iwamoto, Fumihiro Kawai, Hirofumi Ohashi, Senko Tsukuda, Satomi Shimura, Ryosuke Suzuki, Hideki Aizaki, Masaya Sugiyama, Sam-Yong Park, Takayoshi Ito, Naoko Ohtani, Fumio Sugawara, Yasuhito Tanaka, Masashi Mizokami, Camille Sureau, Takaji Wakita
UNLABELLED: Anti-hepatitis B virus (HBV) drugs are currently limited to nucleos(t)ide analogs (NAs) and interferons. A challenge of drug development is the identification of small molecules that suppress HBV infection from new chemical sources. Here, from a fungus-derived secondary metabolite library, we identify a structurally novel tricyclic polyketide, named vanitaracin A, which specifically inhibits HBV infection. Vanitaracin A inhibited the viral entry process with a submicromolar 50% inhibitory concentration (IC50) (IC50 = 0...
December 2015: Journal of Virology
Hironori Nishitsuji, Saneyuki Ujino, Yuko Shimizu, Keisuke Harada, Jing Zhang, Masaya Sugiyama, Masashi Mizokami, Kunitada Shimotohno
A recombinant hepatitis B virus (HBV) expressing NanoLuc (NL) (HBV/NL) was produced by cotransfecting a plasmid containing a 1.2-fold HBV genome carrying the NL gene with a plasmid bearing a packaging-defective 1.2-fold HBV genome into a human hepatoma cell line, HepG2. We found that NL activity in HBV/NL-infected primary hepatocytes or sodium taurocholate cotransporting polypeptide-transduced human hepatocyte-derived cell lines increased linearly for several days after infection and was concordant with HBV RNA levels in the cells...
November 2015: Cancer Science
Annika Sommerfeld, Patrick G K Mayer, Miriam Cantore, Dieter Häussinger
In perfused rat liver, hepatocyte shrinkage induces a Fyn-dependent retrieval of the bile salt export pump (Bsep) and multidrug resistance-associated protein 2 (Mrp2) from the canalicular membrane (Cantore, M., Reinehr, R., Sommerfeld, A., Becker, M., and Häussinger, D. (2011) J. Biol. Chem. 286, 45014-45029) leading to cholestasis. However little is known about the effects of hyperosmolarity on short term regulation of the Na(+)-taurocholate cotransporting polypeptide (Ntcp), the major bile salt uptake system at the sinusoidal membrane of hepatocytes...
October 2, 2015: Journal of Biological Chemistry
Marc Le Vée, Elodie Jouan, Claire Denizot, Yannick Parmentier, Olivier Fardel
Hepatic drug transporters play an important role in pharmacokinetics and drug-drug interactions. Among these membrane transporters, the sodium taurocholate cotransporting polypeptide (NTCP/SLC10A1), the organic anion transporting polypeptides (OATPs) 1B1 (SLCO1B1), 1B3 (SLCO1B3) and 2B1 (SLCO2B1), the organic anion transporter 2 (OAT2/SLC22A7) and the organic cation transporter 1 (OCT1/SLC22A1) are likely major ones, notably mediating sinusoidal uptake of various drugs or endogenous compounds, like bile acids, from blood into hepatocytes...
2015: Methods in Molecular Biology
Koichi Watashi, Takaji Wakita
Entry of hepatitis B (HBV) and hepatitis D viruses (HDV) into a host cell represents the initial step of infection. This process requires multiple steps, including the low-affinity attachment of the virus to the cell surface, followed by high-affinity attachment to specific receptor(s), and subsequent endocytosis-mediated internalization. Within the viral envelope, the preS1 region is involved in receptor binding. Recently, sodium taurocholate cotransporting polypeptide (NTCP) has been identified as an entry receptor of HBV and HDV by affinity purification using a preS1 peptide...
August 2015: Cold Spring Harbor Perspectives in Medicine
Pietro Lampertico, Mala Maini, George Papatheodoridis
There have been great strides in the management of chronic hepatitis B virus (HBV) infection, but considerable challenges remain. The European Association for the Study of the Liver (EASL) convened a special conference focusing on all clinical aspects of the management of this disease. Immigration patterns are having a huge effect on the incidence, prevalence and genotype predominance of HBV in many European countries. In recent years there has been significant progress in our understanding of the virology and immunopathology of HBV, particularly the identification of the entry receptor for HBV conferring its hepatotropism, sodium taurocholate co-transporting polypeptide, and a better understanding of the regulation of the covalently closed circular DNA form of HBV - the major barrier to cure...
November 2015: Journal of Hepatology
Mathias Haag, Ute Hofmann, Thomas E Mürdter, Georg Heinkele, Patrick Leuthold, Antje Blank, Walter E Haefeli, Alexander Alexandrov, Stephan Urban, Matthias Schwab
A novel analytical approach for the targeted profiling of bile acids (BAs) in human serum/plasma based on liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) is presented. Reversed-phase chromatography enabled the baseline separation of 15 human BA species which could be readily detected by accurate mass analysis in negative ion mode. Blood proteins were removed by methanol precipitation in the presence of deuterium-labeled internal standards which allowed BA quantification in 50 μl plasma/serum...
September 2015: Analytical and Bioanalytical Chemistry
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