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The decrease in farnesoid X receptor, pregnane X receptor and constitutive androstane receptor in the liver after

Jiro Ogura1, Yusuke Terada, Takashi Tsujimoto

  • 1Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan.

Journal of Pharmacy & Pharmaceutical Sciences : a Publication of the Canadian Society for Pharmaceutical Sciences, Societe Canadienne Des Sciences Pharmaceutiques
|January 22, 2013
PubMed
Abstract

Insights

Intestinal ischemia-reperfusion decreases liver expression of key nuclear receptors Farnesoid X receptor (FXR), pregnane X receptor (PXR), and constitutive androstane receptor (CAR). Interleukin-6 (IL-6) significantly contributes to these expression decreases.

Area of Science:

  • Hepatology
  • Gastroenterology
  • Molecular Biology

Background:

  • Intestinal ischemia-reperfusion (I/R) injury can lead to remote organ damage, including the liver, potentially causing multi-organ failure.
  • The precise molecular mechanisms driving acute liver injury post-intestinal I/R remain incompletely understood.
  • Farnesoid X receptor (FXR), pregnane X receptor (PXR), and constitutive androstane receptor (CAR) are critical for regulating detoxification pathways and preventing drug-induced liver injury.

Purpose of the Study:

  • To investigate the expression and nuclear localization of FXR, PXR, and CAR in the liver following intestinal I/R.
  • To evaluate the impact of Interleukin-6 (IL-6) on the expression and nuclear localization of these nuclear receptors in vitro.

Main Methods:

  • Establishment of an intestinal I/R rat model.
  • Utilized HepG2 cells for in vitro experiments.
  • Assessed mRNA and protein expression via real-time PCR and Western blotting.
  • Analyzed nuclear receptor localization using Western blotting on nuclear extracts.

Main Results:

  • Intestinal I/R led to decreased expression and nuclear localization of FXR, PXR, and CAR in rat livers, observable as early as 3 hours and significantly by 6 hours post-injury.
  • In vitro, IL-6 treatment of HepG2 cells resulted in dose-dependent decreases in FXR, PXR, and CAR expression and nuclear translocation.
  • Specific IL-6 concentrations (0.5-1 ng/mL for FXR, 0.5-100 ng/mL for PXR, 100 ng/mL for CAR) reduced receptor expression, while varying concentrations affected nuclear localization.

Conclusions:

  • FXR, PXR, and CAR expression and nuclear localization are significantly reduced in the liver after intestinal I/R.
  • Interleukin-6 (IL-6) is identified as a key factor contributing to the downregulation of these crucial nuclear receptors following intestinal I/R.

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