NRF2 and FXR dual signaling pathways cooperatively regulate the effects of oleanolic acid on cholestatic liver injury

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Jianming Liu¹, Jiawei Liu², Chao Meng²

¹Clinical Pharmacology Institute, Pharmaceutical School, Nanchang University, Nanchang 330031, P. R. China; Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang 330006, P. R. China.

Phytomedicine : International Journal of Phytotherapy and Phytopharmacology

|November 7, 2022

Abstract

Background:

Previous studies have shown that the anti-cholestatic effect of oleanolic acid (OA) is associated with FXR and NRF2. However, how the two signaling pathways cooperate to regulate the anti-cholestatic effect of OA remains unclear.

Purpose:

This study aimed to further demonstrate the effect of OA on alpha-naphthyl isothiocyanate (ANIT)-induced cholestatic liver injury and the interaction mechanism between NRF2 and FXR signaling pathways in maintaining bile acid homeostasis.

Methods:

Gene knockout animals and cell models, metabolomics analysis, and co-immunoprecipitation were used to investigate the mechanism of OA against cholestatic liver injury.

Results:

The effect of OA against ANIT-induced liver injury in rats was dramatically reduced after Nrf2 gene knockdown. With the silencing of Fxr, the hepatoprotective effect of OA was weakened, but it still effectively alleviated cholestatic liver injury in rats. In L02 cells, OA can up-regulate the levels of NRF2, FXR, BSEP and UGT1A1, and reduce the expression of CYP7A1. Silencing of NRF2 or FXR significantly attenuated the protective effect of OA on ANIT-induced L02 cell injury and its regulation on downstream target genes, and the influence of NRF2 gene silencing on OA appeared to be greater. The NRF2 activator sulforaphane, and the FXR activator GW4064 both remarkably promoted NRF2 binding to P300 and FXR to RXRα, but reduced β-catenin binding to P300 and β-catenin binding to FXR.

Conclusion:

The effect of OA on cholestatic liver injury is closely related to the simultaneous activation of NRF2 and FXR dual signaling pathways, in which NRF2 signaling pathway plays a more important role. The dual signaling pathways of NRF2 and FXR cooperatively regulate bile acid metabolic homeostasis through the interaction mechanism with β-catenin/P300.

Insights

Oleanolic acid (OA) protects against cholestatic liver injury by activating both NRF2 and FXR pathways, with NRF2 playing a primary role. These pathways cooperate via beta-catenin/P300 interactions to maintain bile acid balance.

Area of Science:

Hepatology and molecular biology
Biochemistry and pharmacology

Background:

Oleanolic acid (OA) exhibits anti-cholestatic effects linked to FXR and NRF2 signaling.
The precise cooperative mechanism of FXR and NRF2 in OA's anti-cholestatic action remains incompletely understood.

Purpose of the Study:

To elucidate the protective effects of OA against alpha-naphthyl isothiocyanate (ANIT)-induced cholestatic liver injury.
To investigate the interaction between NRF2 and FXR signaling pathways in maintaining bile acid homeostasis.

Main Methods:

Utilized gene knockout animal and cell models for mechanistic studies.
Employed metabolomics analysis and co-immunoprecipitation to assess OA's effects.
Investigated the impact of NRF2 and FXR gene silencing on OA's efficacy.

Main Results:

OA's protective effect against ANIT-induced liver injury was diminished by Nrf2 knockdown and weakened by Fxr silencing.
OA upregulated NRF2, FXR, BSEP, and UGT1A1 while downregulating CYP7A1 in L02 cells.
NRF2 and FXR activation promoted specific protein interactions, influencing bile acid homeostasis, with NRF2 showing a greater impact.

Conclusions:

OA's anti-cholestatic effect relies on the synergistic activation of both NRF2 and FXR signaling pathways.
The NRF2 pathway plays a more dominant role in mediating OA's hepatoprotective effects.
Cooperative regulation of bile acid homeostasis by NRF2 and FXR involves interactions with the beta-catenin/P300 complex.

Read full analysis

Keywords:

Cholestatic liver injury Farnesol X receptor (FXR)Interaction Nuclear factor red related factor 2 (NRF2)Oleanolic acid

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