Glucocorticoid receptor regulates organic cation transporter 1 (OCT1,SLC22A1) expression via HNF4a upregulation in primary human hepatocytes

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-4a (hnf4a). hnf4a 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 hnf4a 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 hnf4a 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 hnf4a,ccaat/enhancer binding proteins b (c/ebpb) and peroxisome proliferator-activated receptor- g coactivator 1a (pgc1a) 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/ebpb and hnf4a mrnas expression and that c/ebpb co-transfection stimulates oct1 gene reporter construct in hepg2 cells. nevertheless,neither c/ebpb nor pgc1a were upregulated in human hepatocytes by dexamethasone. conclusion:we can conclude that gr-induced expression of hnf4a may contribute to indirect oct1 gene up-regulation by dexamethasone in primary human hepatocytes,but not in hepatocyte-derived tumor cell lines.copyright © 2013 by institute of pharmacology polish academy of sciences.