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microRNA-206 modulates the hepatic expression of the organic anion-transporting polypeptide 1B1.

Authors
  • El Saadany, Tämer1
  • van Rosmalen, Belle2
  • Gai, Zhibo1, 3
  • Hiller, Christian1
  • Verheij, Joanne4
  • Stieger, Bruno1
  • van Gulik, Thomas2
  • Visentin, Michele1
  • Kullak-Ublick, Gerd A1, 5
  • 1 Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zürich, Switzerland. , (Switzerland)
  • 2 Department of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. , (Netherlands)
  • 3 Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, China. , (China)
  • 4 Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. , (Netherlands)
  • 5 Mechanistic Safety, CMO & Patient Safety, Global Drug Development, Novartis Pharma, Basel, Switzerland. , (Switzerland)
Type
Published Article
Journal
Liver international : official journal of the International Association for the Study of the Liver
Publication Date
Dec 01, 2019
Volume
39
Issue
12
Pages
2350–2359
Identifiers
DOI: 10.1111/liv.14212
PMID: 31408569
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The organic anion-transporting polypeptide 1B1 (OATP1B1) is an anion exchanger expressed at the hepatocyte sinusoidal membrane, which mediates the uptake of several endogenous metabolites and drugs. OATP1B1 expression level and activity are major sources of inter-patient variability of pharmacokinetics and pharmacodynamics of several drugs. Besides the genotype, factors that contribute to the inter-individual variability in OATP1B1 expression level are practically unknown. The aim of this work was to uncover novel epigenetic mechanisms of OATP1B1 regulation. A functional screening strategy to assess the effect of microRNAs on the uptake of estrone-3-sulphate, an OATP1B1 substrate, into human hepatocellular carcinoma (Huh-7) cells was used. microRNA-206 (miR-206) expression in human liver tissues was measured by real-time RT-PCR. OATP1B1 expression in Huh-7 and in human liver tissues was assessed by real-time RT-PCR, Western blotting and immunostaining. The mRNA-miRNA interaction was assessed by reporter assay. miR-206 mimic repressed mRNA and protein expression of OATP1B1 in Huh-7 cells. The intracellular accumulation of estrone-3-sulphate was reduced by 30% in cells overexpressing miR-206. The repressive effect of miR-206 on the activity of the firefly luciferase gene 2 under the control of the OATP1B1 3' untranslated region was lost upon deletion of the predicted miR-206 binding site. Hepatic miR-206 level negatively correlated with OATP1B1 mRNA and protein levels extracted from normal human liver tissues. miR-206 exerts a suppressive effect on OATP1B1 expression by an epigenetic mechanism. Individuals with high hepatic levels of miR-206 appear to display lower level of OATP1B1. © 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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