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Glucocorticoid receptor regulates organic cation transporter 1 (OCT1, SLC22A1) expression via HNF4α upregulation in primary human hepatocytes

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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-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 mRNAand 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/EBPγ 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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Author notes

  1. A.R. and L.K. contributed equally to these studies.

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, Hradec Kralove, CZ-500 05, Czech Republic

    Alice Rulcova, Lucie Krausova, Tomas Smutny, Radim Vrzal & Petr Pavek

  2. Department of Cell Biology and Genetics, Faculty of Science, Palacky University in Olomouc, Slechtitelu 11, Olomouc, CZ-783 71, Czech Republic

    Zdenek Dvorak

  3. Unidad Mixta Hepatología Experimental, Hospital La Fe & University of Valencia (Dep. Biochemistry and Molecular Biology), Av. Campanar, 21, 46009, Valencia, Spain

    Ramiro Jover

  4. CIBERehd, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain

    Ramiro Jover

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  1. Alice Rulcova
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Rulcova, A., Krausova, L., Smutny, T. et al. Glucocorticoid receptor regulates organic cation transporter 1 (OCT1, SLC22A1) expression via HNF4α upregulation in primary human hepatocytes. Pharmacol. Rep 65, 1322–1335 (2013). https://doi.org/10.1016/S1734-1140(13)71491-9

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  • DOI: https://doi.org/10.1016/S1734-1140(13)71491-9

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