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Statements

Subject Item
n2:RIV%2F61989592%3A15310%2F13%3A33147782%21RIV14-GA0-15310___
rdf:type
skos:Concept n14:Vysledek
rdfs:seeAlso
http://www.if-pan.krakow.pl/pjp/pdf/2013/5_1322.pdf
dcterms:description
Organic cation transporter 1 (OCT1, SLC22A1) is a membrane transporter that is important for therapeutic effect of the antidiabetic drug metformin. Its liver-specific expression in hepatocytes is strongly controlled by hepatocyte nuclear factor-4alfa (HNF4alfa). HNF4alfa expression and transcriptional activity have been demonstrated to be augmented by glucocorticoid receptor (GR) in human hepatocytes and rodent livers. It was examined whether GR activation indirectly induces OCT1 gene expression via HNF4alfa up-regulation in primary human hepatocytes. We also examined which other transcription factors are involved in OCT1 gene expression and whether they are regulated by dexamethasone using qRT-PCR and gene reporter assays. RESULTS: We found that dexamethasone significantly up-regulates OCT1 mRNA and protein in normal primary human hepatocytes, but not in hepatocyte-derived tumor cell lines HepG2 and MZ-Hep1. Consistently, we observed that HNF4alfa is induced by dexamethasone in primary human hepatocytes, but not in hepatocyte tumor-derived cell lines. Viral transduction of MZ-Hep1 cells with the expression constructs for HNF4alfa, CCAAT/enhancer binding proteins beta (C/EBPbeta) and peroxisome proliferator-activated receptor-gama coactivator 1alfa (PGC1alfa) demonstrated significant roles of the transcription factors in OCT1 gene regulation. We found that expression of OCT1 mRNA in human livers significantly correlates with C/EBPbeta and HNF4alfa mRNAs expression and that C/EBPbeta co-transfection stimulates OCT1 gene reporter construct in HepG2 cells. Nevertheless, neither C/EBPbeta nor PGC1alfa were upregulated in human hepatocytes by dexamethasone. CONCLUSION: We can conclude that GR-induced expression of HNF4alfa may contribute to indirect OCT1 gene up-regulation by dexamethasone in primary human hepatocytes, but not in hepatocyte-derived tumor cell lines. Organic cation transporter 1 (OCT1, SLC22A1) is a membrane transporter that is important for therapeutic effect of the antidiabetic drug metformin. Its liver-specific expression in hepatocytes is strongly controlled by hepatocyte nuclear factor-4alfa (HNF4alfa). HNF4alfa expression and transcriptional activity have been demonstrated to be augmented by glucocorticoid receptor (GR) in human hepatocytes and rodent livers. It was examined whether GR activation indirectly induces OCT1 gene expression via HNF4alfa up-regulation in primary human hepatocytes. We also examined which other transcription factors are involved in OCT1 gene expression and whether they are regulated by dexamethasone using qRT-PCR and gene reporter assays. RESULTS: We found that dexamethasone significantly up-regulates OCT1 mRNA and protein in normal primary human hepatocytes, but not in hepatocyte-derived tumor cell lines HepG2 and MZ-Hep1. Consistently, we observed that HNF4alfa is induced by dexamethasone in primary human hepatocytes, but not in hepatocyte tumor-derived cell lines. Viral transduction of MZ-Hep1 cells with the expression constructs for HNF4alfa, CCAAT/enhancer binding proteins beta (C/EBPbeta) and peroxisome proliferator-activated receptor-gama coactivator 1alfa (PGC1alfa) demonstrated significant roles of the transcription factors in OCT1 gene regulation. We found that expression of OCT1 mRNA in human livers significantly correlates with C/EBPbeta and HNF4alfa mRNAs expression and that C/EBPbeta co-transfection stimulates OCT1 gene reporter construct in HepG2 cells. Nevertheless, neither C/EBPbeta nor PGC1alfa were upregulated in human hepatocytes by dexamethasone. CONCLUSION: We can conclude that GR-induced expression of HNF4alfa may contribute to indirect OCT1 gene up-regulation by dexamethasone in primary human hepatocytes, but not in hepatocyte-derived tumor cell lines.
dcterms:title
Glucocorticoid receptor regulates organic cation transporter 1 (OCT1, SLC22A1) expression via HNF4alfa upregulation in primary human hepatocytes Glucocorticoid receptor regulates organic cation transporter 1 (OCT1, SLC22A1) expression via HNF4alfa upregulation in primary human hepatocytes
skos:prefLabel
Glucocorticoid receptor regulates organic cation transporter 1 (OCT1, SLC22A1) expression via HNF4alfa upregulation in primary human hepatocytes Glucocorticoid receptor regulates organic cation transporter 1 (OCT1, SLC22A1) expression via HNF4alfa upregulation in primary human hepatocytes
skos:notation
RIV/61989592:15310/13:33147782!RIV14-GA0-15310___
n14:predkladatel
n15:orjk%3A15310
n3:aktivita
n19:P
n3:aktivity
P(GAP303/12/0472), P(GBP303/12/G163)
n3:cisloPeriodika
5
n3:dodaniDat
n8:2014
n3:domaciTvurceVysledku
n5:8069239 n5:4908171
n3:druhVysledku
n16:J
n3:duvernostUdaju
n10:S
n3:entitaPredkladatele
n17:predkladatel
n3:idSjednocenehoVysledku
76704
n3:idVysledku
RIV/61989592:15310/13:33147782
n3:jazykVysledku
n13:eng
n3:klicovaSlova
hepatocytes; human; primary; upregulation; HNF4alfa; via; expression; SLC22A1; OCT1; transporter; cation; organic; regulates; receptor; Glucocorticoid
n3:klicoveSlovo
n7:OCT1 n7:regulates n7:hepatocytes n7:SLC22A1 n7:organic n7:Glucocorticoid n7:human n7:primary n7:receptor n7:via n7:expression n7:HNF4alfa n7:transporter n7:cation n7:upregulation
n3:kodStatuVydavatele
PL - Polská republika
n3:kontrolniKodProRIV
[83987BCF7D44]
n3:nazevZdroje
Pharmacological Reports
n3:obor
n18:FR
n3:pocetDomacichTvurcuVysledku
2
n3:pocetTvurcuVysledku
7
n3:projekt
n11:GBP303%2F12%2FG163 n11:GAP303%2F12%2F0472
n3:rokUplatneniVysledku
n8:2013
n3:svazekPeriodika
65
n3:tvurceVysledku
Rulcová, Alice Krausová, Lucie Dvořák, Zdeněk Pávek, Petr Jover, Ramiro Smutný, Tomáš Vrzal, Radim
n3:wos
000330815700028
s:issn
1734-1140
s:numberOfPages
14
n20:organizacniJednotka
15310