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Oleanolic Acid and Ursolic Acid Induce UGT1A1 Expression in HepG2 Cells by Activating PXR Rather Than CAR

Na Yao1, Caiwen Zeng2, Tao Zhan1

  • 1Clinical Pharmacology Institute, Nanchang University, Nanchang, China.

Frontiers in Pharmacology
|October 16, 2019
PubMed

Insights

Oleanolic acid (OA) and ursolic acid (UA) significantly increase the expression of UGT1A enzymes in liver cells. This induction of UGT1A1 is primarily mediated by the pregnane X receptor (PXR) pathway.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Hepatology

Background:

  • Oleanolic acid (OA) and ursolic acid (UA) are natural compounds with known biological activities.
  • Previous studies showed OA and UA affect UGT1A enzyme activity but not their expression.
  • The regulatory mechanisms of OA and UA on UGT1A expression in HepG2 cells were unclear.

Purpose of the Study:

  • To investigate the effect of OA and UA on the expression of UDP-glucuronosyltransferases (UGT1As) in HepG2 cells.
  • To elucidate the regulatory mechanisms of OA and UA on UGT1A1 expression via pregnane X receptor (PXR) and constitutive androstane receptor (CAR) signaling pathways.

Main Methods:

  • Quantitative PCR (Q-PCR) and Western blotting to analyze gene and protein expression.
  • Dual-luciferase reporter gene assays to assess PXR and CAR activity.
  • Silencing of PXR and CAR in HepG2 cells to determine their roles in UGT1A1 regulation.

Main Results:

  • OA and UA significantly induced the expression of UGT1A1, UGT1A3, UGT1A4, and UGT1A9 in HepG2 cells.
  • Both compounds upregulated PXR expression but did not affect CAR expression.
  • OA and UA promoted PXR-mediated UGT1A1 activity, with PXR silencing abolishing the induction.
  • UGT1A1 expression was elevated in CAR-silenced cells, suggesting a PXR-dependent mechanism.

Conclusions:

  • OA and UA induce the expression of multiple UGT1A isoforms in HepG2 cells.
  • The induction of UGT1A1 by OA and UA is mediated through the activation of the PXR signaling pathway.
  • CAR signaling is not involved in the regulation of UGT1A1 expression by OA and UA.
Keywords:
CAROAPXRUAUGT1A1

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