Glucocorticoid receptor regulates organic cation transporter 1 (OCT1, SLC22A1) expression via HNF4α upregulation in primary human hepatocytes
Language English Country Switzerland Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
24399729
DOI
10.1016/s1734-1140(13)71491-9
PII: S1734-1140(13)71491-9
Knihovny.cz E-resources
- MeSH
- Hep G2 Cells MeSH
- Time Factors MeSH
- Dexamethasone pharmacology MeSH
- Glucocorticoids pharmacology MeSH
- Hepatocyte Nuclear Factor 4 genetics metabolism MeSH
- Hepatocytes drug effects metabolism MeSH
- Humans MeSH
- RNA, Messenger metabolism MeSH
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha MeSH
- Organic Cation Transporter 1 genetics metabolism MeSH
- Primary Cell Culture MeSH
- CCAAT-Enhancer-Binding Protein-beta genetics metabolism MeSH
- Receptors, Glucocorticoid agonists metabolism MeSH
- Transduction, Genetic MeSH
- Transfection MeSH
- Transcription Factors genetics metabolism MeSH
- Up-Regulation MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- CEBPB protein, human MeSH Browser
- Dexamethasone MeSH
- Glucocorticoids MeSH
- Hepatocyte Nuclear Factor 4 MeSH
- HNF4A protein, human MeSH Browser
- RNA, Messenger MeSH
- NR3C1 protein, human MeSH Browser
- PPARGC1A protein, human MeSH Browser
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha MeSH
- Organic Cation Transporter 1 MeSH
- CCAAT-Enhancer-Binding Protein-beta MeSH
- Receptors, Glucocorticoid MeSH
- Transcription Factors MeSH
BACKGROUND: 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-4α (HNF4α). HNF4α expression and transcriptional activity have been demonstrated to be augmented by glucocorticoid receptor (GR) in human hepatocytes and rodent livers. METHODS: It was examined whether GR activation indirectly induces OCT1 gene expression via HNF4α 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 HNF4α 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 HNF4α, CCAAT/enhancer binding proteins β (C/EBPβ) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) 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/EBPβ and HNF4α mRNAs expression and that C/EBPβ co-transfection stimulates OCT1 gene reporter construct in HepG2 cells. Nevertheless, neither C/EBPβ nor PGC1α were upregulated in human hepatocytes by dexamethasone. CONCLUSION: We can conclude that GR-induced expression of HNF4α may contribute to indirect OCT1 gene up-regulation by dexamethasone in primary human hepatocytes, but not in hepatocyte-derived tumor cell lines.
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