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Baohuoside I inhibits FXR signaling pathway to interfere with bile acid homeostasis via targeting ER α degradation

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Abstract

Epimedii folium (EF) is an effective herbal medicine in osteoporosis treatment, but the clinical utilization of EF has been limited due to potential hepatotoxicity. The previous studies identified that baohuoside I (BI), the main active component of EF, was relevant to EF-induced liver injury. However, the mechanisms of BI causing direct injury to hepatocytes remain unclear. Here, we reveal that BI inhibits FXR-mediated signaling pathway via targeting estrogen receptor α (ER α), leading to the accumulation of bile acids (BAs). Targeted bile acid analyses show BI alters the BA composition and distribution, resulting in impaired BA homeostasis. Mechanistically, BI induces FXR-dependent hepatotoxicity at transcriptional level. Additionally, ER α is predicted to bind to the FXR promoter region based on transcription factor binding sites databases and we further demonstrate that ER α positively regulates FXR promoter activity and affects the expression of target genes involved in BA metabolism. Importantly, we discover that ER α and its mediated FXR transcription regulation might be involved in BI-induced liver injury via ligand-dependent ER α degradation. Collectively, our findings indicate that FXR is a newly discovered target gene of ER α mediated BI-induced liver injury, and suggest BI may be responsible for EF-induced liver injury.

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Data availability

Data is available on request from the authors. The data that support the findings of this study are available from the corresponding author upon reasonable request. Some data may not be made available because of privacy or ethical restrictions. All data generated or analyzed during this study are included either in this article or in the supplemental materials.

Code availability

Not applicable.

Abbreviations

EF:

Epimedii folium

ER α:

Estrogen receptor alpha

FXR:

Farnesoid X receptor

TGR5:

G protein-coupled bile acid receptor 1

TCM:

Traditional Chinese medicine

BA:

Bile acid

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

ALP:

Alkaline phosphatase

TBA:

Total bile acid

Tbil:

Total bilirubin

Dbil:

Direct bilirubin

TC:

Total cholesterol

LDH:

Lactate dehydrogenase

ROS:

Reactive oxygen species

MPP:

Mitochondrial membrane potential

NLRP3:

Nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3

CCK8:

Cell counting kit-8

H&E:

Hematoxylin-eosin

FBS:

Fetal bovine serum

HRP:

Horseradish peroxidase

IC50 :

The half maximal inhibitory concentration

FITC:

Fluorescein isothiocyanate

CYP7A1:

Cytochrome P450 family 7 subfamily A member 1

CYP8B1:

Cytochrome P450 family 8, subfamily B polypeptide 1

NTCP:

Sodium/taurocholate cotransporting polypeptide

OATP:

Solute carrier organic anion transporter family member 1A2

BSEP:

ATP binding cassette subfamily B member 11

MRP2:

ATP binding cassette subfamily C member 2

ICP:

Intrahepatic cholestasis of pregnancy

BDL:

Bile duct ligation

TGM2:

Transglutaminase 2

GDF15:

Growth differentiation factor 15

E2 :

17β-Estradiol

SULT1E1:

Sulfotransferase family 1E member 1

SHP:

Nuclear receptor subfamily 0 group B member 2

ChIP:

Chromatin immunoprecipitation

EMSA:

Electrophoretic mobility shift assay

RT:

Room temperature

CRISPR:

Clustered regularly interspaced short palindromic repeats

Cas9:

CRISPR-associated 9

DMEM:

Dulbecco’s modified Eagle’s medium

DMSO:

Dimethyl sulfoxide

CHX:

Cycloheximide

gRNA:

Guide RNA

SDS-PAGE:

Sodium dodecyl sulfate–polyacrylamide gel electrophoresis

TBST:

Tris-buffered saline with Tween solution

NC:

Negative control

NS:

No significance

KO:

Knockout

WT:

Wild type

MST:

Microscale thermophoresis

DAPI:

4’,6-Diamidino-2-phenylindole

CA:

Cholic acid

CDCA:

Chenodeoxycholic acid

DCA:

Deoxycholic acid

HDCA:

Hyodeoxycholic acid

LCA:

Lithocholic acid

MCA:

Muricholic acid

T:

Taurine

G:

Glycine

UDCA:

Ursodeoxycholic acid

References

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Acknowledgements

We are grateful to the State Key Laboratory of Natural Medicines for providing the experimental platform and thanks to the lab staff for their help.

Funding

This work was supported by the National Natural Science Foundation of China (No. 82174070).

Author information

Authors and Affiliations

Authors

Contributions

Study conception and design: Zhen Zhao, Hui-Jun Li; foundation support: Hui-Jun Li, Ping Li, Yan Jiang; acquisition of data: Zhen Zhao, Jin-Fa Du, Lu-Lu Yang; material support: Jin-Fa Du, Qiao-Lei Wang; analysis and interpretation of data: Zhen Zhao, Jin-Fa Du, Lu-Lu Yang, Hui-Jun Li, Zu-Guo Zheng; drafting of the manuscript: Zhen Zhao, Hui-Jun Li; critical revision: Zhen Zhao, Qiao-Lei Wang, Jin-Fa Du, Hui-Jun Li, Lu-Lu Yang, Zu-Guo Zheng.

Corresponding authors

Correspondence to Yan Jiang or Hui-Jun Li.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Ethics approval

All animal protocols were approved by the Institutional Animal Care and Use Committee of China Pharmaceutical University and the Laboratory Animal Management Committee of Jiangsu Province (Nanjing, China).

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Written informed consents were collected from all the participants before enrollment.

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All contributing authors agree to the publication of this article.

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Graphical headlights

BI represses the downstream target genes of FXR related to BAs metabolism, leading to impaired BA flow and BA accumulation in hepatocytes.

FXR is identified as a newly discovered target gene of ER α.

BI facilitates ligand-dependent protein degradation via targeting ER α, resulting in transcription repression of FXR.

Supplementary Information

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Supplementary file1 (DOCX 2.27 MB)

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Zhao, Z., Yang, LL., Wang, QL. et al. Baohuoside I inhibits FXR signaling pathway to interfere with bile acid homeostasis via targeting ER α degradation. Cell Biol Toxicol 39, 1215–1235 (2023). https://doi.org/10.1007/s10565-022-09737-x

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  • DOI: https://doi.org/10.1007/s10565-022-09737-x

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