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Functional inhibition of Oct leads to HNF4α upregulation

  • Authors:
    • Johanna Vollmar
    • Yong Ook Kim
    • Jens Uwe Marquardt
    • Peter R. Galle
    • Detlef Schuppan
    • Tim Zimmermann
  • View Affiliations / Copyright

    Affiliations: Department of Internal Medicine II, Hospital of Worms, D-67550 Worms, Germany, Institute of Translational Immunology, Fibrosis and Metabolism Centre, Johannes Gutenberg‑University Mainz, D-55131 Mainz, Germany, Department of Internal Medicine I, University Hospital Schleswig‑Holstein, D-23538 Lübeck, Germany, 1st Department of Internal Medicine, Gastroenterology and Hepatology, University Medical Centre, Johannes Gutenberg‑University Mainz, D-55131 Mainz, Germany
    Copyright: © Vollmar et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 349
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    Published online on: February 11, 2021
       https://doi.org/10.3892/etm.2021.9780
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Abstract

Organic cation transporters (human, OCT; mouse, Oct) are responsible for the intracellular uptake and detoxification of a broad spectrum of endogenous and exogenous substrates. The OCT1 gene SLC22A1 (human; mouse, Scl22a1) is transactivated by hepatocyte nuclear factor 4α (human, HNF4α; mouse, Hnf4α). HNF4α is a master regulator of hepatocyte differentiation and is frequently associated with hepatocellular carcinoma (HCC). In addition, the downregulation of HNF4α is associated with enhanced fibrogenesis. Our recent study revealed that hepatocarcinogenesis and fibrosis were enhanced with the loss of Oct3 (gene, Slc22a3). Notably, differences in Hnf4α expression, and in cholestasis and fibrosis were also detected in Oct3‑knockout (FVB.Slc22a3tm10pb, Oct3‑/‑) mice. To the best of our knowledge, no data exists on an interaction between Oct3 and Hnf4α. We hypothesised that loss of Oct3 may have an impact on Hnf4α expression. In the present study, gene expression analyses were performed in liver tissue from untreated Oct3‑/‑ and wild type (FVB, WT) mice. C57BL/6, Oct3‑/‑ and WT mice were treated with pro‑fibrotic carbon tetrachloride (CCl4) or thioacetamide (TAA) for 6 weeks to chemically induce liver fibrosis. Cholestasis‑associated fibrosis was mechanically generated in Oct3‑/‑ and WT mice by bile duct ligation (BDL). Finally, stably OCT1‑ and OCT3‑transfected tumour cell lines and primary murine hepatocytes were treated with the non‑selective OCT inhibitor quinine and Hnf4α expression was quantified by qPCR and immunofluorescence. The results revealed that Hnf4α is one of the top upstream regulators in Oct3‑/‑ mice. Hnf4α mRNA expression levels were downregulated in Oct3‑/‑ mice compared with in WT mice during cholestatic liver damage as well as fibrogenesis. The downregulation of Hnf4α mRNA expression in fibrotic liver tissue was reversible within 4 weeks. In stably OCT1‑ and OCT3‑transfected HepG2 and HuH7 cells, and primary murine hepatocytes, functional inhibition of OCT led to the upregulation of Hnf4α mRNA expression. Hnf4α was revealed to be located in the cytosol of WT hepatocytes, whereas Oct3‑/‑ hepatocytes exhibited nuclear Hnf4α expression. In conclusion, Hnf4α was downregulated in response to cholestasis and fibrosis, and functional inhibition of Oct may lead to the upregulation of Hnf4α.
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Copy and paste a formatted citation
Spandidos Publications style
Vollmar J, Kim Y, Marquardt JU, Galle PR, Schuppan D and Zimmermann T: Functional inhibition of Oct leads to HNF4α upregulation. Exp Ther Med 21: 349, 2021.
APA
Vollmar, J., Kim, Y., Marquardt, J.U., Galle, P.R., Schuppan, D., & Zimmermann, T. (2021). Functional inhibition of Oct leads to HNF4α upregulation. Experimental and Therapeutic Medicine, 21, 349. https://doi.org/10.3892/etm.2021.9780
MLA
Vollmar, J., Kim, Y., Marquardt, J. U., Galle, P. R., Schuppan, D., Zimmermann, T."Functional inhibition of Oct leads to HNF4α upregulation". Experimental and Therapeutic Medicine 21.4 (2021): 349.
Chicago
Vollmar, J., Kim, Y., Marquardt, J. U., Galle, P. R., Schuppan, D., Zimmermann, T."Functional inhibition of Oct leads to HNF4α upregulation". Experimental and Therapeutic Medicine 21, no. 4 (2021): 349. https://doi.org/10.3892/etm.2021.9780
Copy and paste a formatted citation
x
Spandidos Publications style
Vollmar J, Kim Y, Marquardt JU, Galle PR, Schuppan D and Zimmermann T: Functional inhibition of Oct leads to HNF4α upregulation. Exp Ther Med 21: 349, 2021.
APA
Vollmar, J., Kim, Y., Marquardt, J.U., Galle, P.R., Schuppan, D., & Zimmermann, T. (2021). Functional inhibition of Oct leads to HNF4α upregulation. Experimental and Therapeutic Medicine, 21, 349. https://doi.org/10.3892/etm.2021.9780
MLA
Vollmar, J., Kim, Y., Marquardt, J. U., Galle, P. R., Schuppan, D., Zimmermann, T."Functional inhibition of Oct leads to HNF4α upregulation". Experimental and Therapeutic Medicine 21.4 (2021): 349.
Chicago
Vollmar, J., Kim, Y., Marquardt, J. U., Galle, P. R., Schuppan, D., Zimmermann, T."Functional inhibition of Oct leads to HNF4α upregulation". Experimental and Therapeutic Medicine 21, no. 4 (2021): 349. https://doi.org/10.3892/etm.2021.9780
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