Gardenia Iridoid Glucosides Protect Against α-Naphthalene Isothiocya-Nate-Induced Cholestatic Rats Through Activation of the FXR-SHP Signaling Pathway

Meng Xu; Ke Che; Cong Wang; Ya-Ru Chen; Meng-Yuan Chen; Guang-Lei Zhang; Hao Yu; Hao-Nan Xu; Ya-Bao Li; Ping Sheng; Hao Chen

doi:10.2147/CEG.S438234

Gardenia Iridoid Glucosides Protect Against α-Naphthalene Isothiocya-Nate-Induced Cholestatic Rats Through Activation of the FXR-SHP Signaling Pathway

Clin Exp Gastroenterol. 2023 Dec 8:16:225-236. doi: 10.2147/CEG.S438234. eCollection 2023.

Authors

Meng Xu^#¹, Ke Che^#¹, Cong Wang^#², Ya-Ru Chen¹, Meng-Yuan Chen¹, Guang-Lei Zhang¹, Hao Yu³, Hao-Nan Xu¹, Ya-Bao Li¹, Ping Sheng¹, Hao Chen¹

Affiliations

¹ College of Life and Health Sciences, Anhui Science and Technology University, Fengyang, 233100, People's Republic of China.
² School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, 210094, People's Republic of China.
³ Bozhou University, Bozhou, 236800, People's Republic of China.

^# Contributed equally.

Abstract

Introduction: Cholestasis is a common liver disorder that currently has limited treatment options. Gardenia Iridoid Glucosides (GIG) have been found to possess various physiological activities, such as cholagogic, hypoglycemic, antibacterial, and anti-inflammatory effects. The objective of this study was to investigate the effects of GIG on bile acid enterohepatic circulation and explore the underlying mechanism in cholestatic rats.

Methods: In order to identify key pathways associated with cholestasis, we conducted Gene Ontology (GO) Enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. In vivo experiments were then performed on alpha-naphthylisothiocyanate (ANIT)-treated rats to assess the impact of GIG. We measured bile flow and various biomarkers including total bilirubin (TB), total bile acids (TBA), total cholesterol (TC), malondialdehyde (MDA), glutamic-pyruvic transaminase (GPT), glutamic oxaloacetic transaminase (GOT), and total superoxide dismutase (T-SOD) in the serum. We also examined the expression levels of bile salt export pump (BSEP), ATP-binding cassette subfamily B member 4 (ABCB4), far-nesoid X receptor (FXR), small heterodimer partner (SHP), cholesterol 7α-hydroxylase (CYP7A1), and sodium taurocholate cotransporting polypeptide (NTCP) in liver tissue. In vitro experiments were conducted on primary hepatocytes to further investigate the mechanism of action of GIG on the expression of SHP, CYP7A1, NTCP, and FXR.

Results: Our in vivo experiments demonstrated that GIG significantly increased bile flow and reduced the levels of TB, TBA, TC, MDA, GPT, and GOT, while increasing T-SOD levels in ANIT-treated rats. Addi-tionally, GIG ameliorated liver tissue damage induced by ANIT, upregulated the expression of BSEP and ABCB4, and modulated the protein expression of FXR, SHP, CYP7A1, and NTCP in model rats. In vitro experiments further revealed that GIG inhibited the expression of SHP, CYP7A1, and NTCP by suppressing the expression of FXR.

Conclusion: This study provides new insights into the therapeutic potential of GIG for the treatment of cholestasis. GIG demonstrated beneficial effects on bile acid enterohepatic circulation and liver biomarkers in cholestatic rats. The modulation of FXR and its downstream targets may contribute to the mechanism of action of GIG. These findings highlight the potential of GIG as a therapeutic intervention for cholangitis.

Keywords: FXR; Gardenia Iridoid Glucosides; SHP; cholestasis.

Grants and funding

This study was supported by the Project of Natural Science Foundation of Anhui Province (2008085QH395), the major natural science research projects in Anhui Universities (KJ2020ZD011), the Anhui province university outstanding young talent support project (Gxyq2021198), research and development of a feed additive for respiratory diseases and immune enhancement in broilers (horizontal cooperation project: 881383),research on the development of antioxidant functional tea and B2C operation mode technology (horizontal cooperation project: 881384).