Glucocorticoid receptor regulates organic cation transporter 1 (OCT1, SLC22A1) expression via HNF4alpha upregulation in primary human hepatocytes.
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Rulcova A, Krausova L, Smutny T, Vrzal R, Dvorak Z, Jover R, Pavek P
Glucocorticoid receptor regulates organic cation transporter 1 (OCT1, SLC22A1) expression via HNF4alpha upregulation in primary human hepatocytes.
Pharmacol Rep. 2013;65(5):1322-35.
- PubMed ID
- 24399729 [ View in PubMed]
- Abstract
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-4alpha (HNF4alpha). HNF4alpha 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 HNF4alpha 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 HNF4alpha 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 HNF4alpha, CCAAT/enhancer binding proteins beta (C/EBPbeta) and peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC1alpha) 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 HNF4alpha mRNAs expression and that C/EBPbeta co-transfection stimulates OCT1 gene reporter construct in HepG2 cells. Nevertheless, neither C/EBPbeta nor PGC1alpha were upregulated in human hepatocytes by dexamethasone. CONCLUSION: We can conclude that GR-induced expression of HNF4alpha may contribute to indirect OCT1 gene up-regulation by dexamethasone in primary human hepatocytes, but not in hepatocyte-derived tumor cell lines.