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

Rulcova, Alice; Krausová, Lucie; Smutný, Tomás̆; Vrzal, Radim; Dvořák, Zdeněk; Jover, Ramiro; Pávek, Petr

doi:10.1016/s1734-1140(13)71491-9

Cited by 29 publications

(25 citation statements)

References 36 publications

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“…Our recent experiments dealing with viral transduction of MZ-Hep1 cells with the expression constructs for HNF4a, CCAAT/enhancer binding proteins b and peroxisome proliferator-activated receptor-c coactivator 1a revealed significant roles of the transcription factors in SLC22A1 gene regulation (Rulcova et al, 2013). In addition, we found that the expression of OCT1 mRNA in human liver significantly correlates with C/EBPb and HNF4a mRNAs expression and that C/EBPb co-transfection stimulates OCT1 gene reporter construct in HepG2 cells.…”

Section: Regulation Of Basal Hepatic Expressionmentioning

confidence: 68%

“…Luciferase gene reporter construct with 2 kb SLC22A1 promoter sequence; however, was not transactivated by glucocorticoid receptor activation with DEX in hepatic cell lines indicating no direct transactivation via GR. The HNF4a mRNA induction by DEX was totally inhibited by the glucocorticoid receptor antagonist RU486 (Rulcova et al, 2013;Vrzal et al, 2009). HNF4a mRNA up-regulation by glucocorticoids was also described by others in primary human hepatocytes (Godoy et al, 2010;Onica et al, 2008).…”

Section: Ligand-dependent Nuclear Receptor-mediated Regulationmentioning

confidence: 94%

“…In contrast, neither C/EBPb nor PGC1a involved in SLC22A1 gene regulation were up-regulated in human hepatocytes by DEX (Rulcova et al, 2013). Based on these observation, we hypothesized that GRinduced up-regulation of HNF4a by DEX indirectly induces SLC22A1 gene expression in primary human hepatocytes (Figure 3(A)) (Rulcova et al, 2013).…”

Section: Ligand-dependent Nuclear Receptor-mediated Regulationmentioning

confidence: 95%

“…Indeed, the hepatocyte-specific expression of OCT1 is strongly controlled by the hepatocyte nuclear factor 4a (NR2A1), which belongs to genes of the nuclear receptor superfamily (Kamiyama et al, 2007;Rulcova et al, 2013;Saborowski et al, 2006). In a study with primary human hepatocytes, where HNF4a was silenced using an adenovirus-mediated HNF4a-small interfering RNA, it was found that OCT1 is the drug transporter whose expression is most significantly affected by HNF4a silencing (Kamiyama et al, 2007).…”

Section: Regulation Of Basal Hepatic Expressionmentioning

confidence: 99%

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Expression of organic cation transporter 1 (OCT1): unique patterns of indirect regulation by nuclear receptors and hepatospecific gene regulation

Hyršová

Smutný

Trejtnar

et al. 2016

Drug Metabolism Reviews

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The organic cation transporter 1 (OCT1) is the dominant carrier of organic cationic drugs and some positively charged endogenous compounds into hepatocytes. OCT1 has unique expression pattern. It has the highest expression among drug transporters in normal human hepatocytes with large interindividual variability, but it has negligible expression in other tissues or their tumors. Nowadays, it is clear that the regulation of SLC22A1 gene encoding OCT1 transporter is rather complex and that transactivation with hepatocyte nuclear factor 4α (HNF4α) and CCAAT-enhancer-binding protein (C/EBPs) transcription factors as well as epigenetic regulation contribute to its unique hepatocyte-specific expression pattern. Unfortunately, species- and tissue-specific regulation of OCT1 and its orthologs as well as significant down-regulation in most immortalized cell lines hamper the study of SLC22A1 gene regulation. In the current review, we summarize our current understanding of human OCT1 transporter hepatic gene regulation and we propose potential post-transcriptional regulation by predicted miRNAs. We also discuss in detail recent findings on indirect regulation of the transporter via farnesoid X receptor (FXR), glucocorticoid receptor and pregnane X (PXR) receptor, which point out to potential novel mechanisms of xenobiotic-transporting and drug-metabolizing proteins regulation in the human liver as well as to potentially novel drug-drug interaction mechanisms. We also propose that comprehensive understanding of mechanisms of SLC22A1 gene regulation could direct research for other drug transporters and drug-metabolizing enzymes highly expressed in hepatocytes and controlled by HNF4α or other liver-enriched transcription factors.

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Section: Regulation Of Basal Hepatic Expressionmentioning

confidence: 68%

Section: Ligand-dependent Nuclear Receptor-mediated Regulationmentioning

confidence: 94%

Section: Ligand-dependent Nuclear Receptor-mediated Regulationmentioning

confidence: 95%

Section: Regulation Of Basal Hepatic Expressionmentioning

confidence: 99%

See 2 more Smart Citations

Expression of organic cation transporter 1 (OCT1): unique patterns of indirect regulation by nuclear receptors and hepatospecific gene regulation

Hyršová

Smutný

Trejtnar

et al. 2016

Drug Metabolism Reviews

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“…They revealed that dexamethasone administration induced the expression of cytokine, chemokine, and complement family members while repressing the expression of adaptive immune-related genes. Other studies showed alterations of gene expression induced by dexamethasone in a variety of human cells such as hepatocytes [4], glomerular podocytes [5], and mesenchymal stem cells [6]. To shed light on the effect and action mechanism of dexamethasone, we examined the alterations of gene expression levels caused by oral administration of dexamethasone in human subjects.…”

Section: Increased Protein and Mrna Expression Of Resistin After Dexamentioning

confidence: 99%

Increased Protein and mRNA Expression of Resistin After Dexamethasone Administration

et al. 2014

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Synthetic glucocorticoids such as dexamethasone are widely used to treat a variety of inflammatory and autoimmune conditions, but they may induce adverse events including hyperglycemia. To shed light on the effect and action mechanism of dexamethasone, we examined the alterations of gene expression levels caused by dexamethasone.Microarray analysis was performed on whole blood collected from 24 physically healthy subjects at baseline and after dexamethasone administration. The expression levels of resistin mRNA were found to be significantly increased after the dexamethasone administration. In a separate sample of 12 subjects, we examined plasma resistin protein levels and found that they were increased after dexamethasone administration. Furthermore, the plasma mRNA and protein levels of resistin were significantly higher in individuals who carried the A allele of RETN single nucleotide polymorphism rs3219175 than in those who did not carry the allele. There was no significant interaction between the genotype and dexamethasone administration. No significant correlation was found between plasma levels of cortisol and resistin. Consistent with previous studies, the genotype of RETN rs3219175 was a strong determinant of resistin levels. The present study showed that oral administration of dexamethasone increases the protein and mRNA levels of resistin irrespective of the rs3219175 genotype.

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Organic Cation Transporter (OCT/OCTN) Expression at Brain Barrier Sites: Focus on CNS Drug Delivery

Betterton

Davis

Ronaldson

2021

Handbook of Experimental Pharmacology

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

Abstract: 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.

Cited by 29 publications

References 36 publications

Expression of organic cation transporter 1 (OCT1): unique patterns of indirect regulation by nuclear receptors and hepatospecific gene regulation

Expression of organic cation transporter 1 (OCT1): unique patterns of indirect regulation by nuclear receptors and hepatospecific gene regulation

Increased Protein and mRNA Expression of Resistin After Dexamethasone Administration

Organic Cation Transporter (OCT/OCTN) Expression at Brain Barrier Sites: Focus on CNS Drug Delivery

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