The interaction between polyphyllin I and SQLE protein induces hepatotoxicity through SREBP-2/HMGCR/SQLE/LSS pathway
- Author:
Zhiqi LI
1
;
Qiqi FAN
;
Meilin CHEN
;
Ying DONG
;
Farong LI
;
Mingshuang WANG
;
Yulin GU
;
Simin GUO
;
Xianwen YE
;
Jiarui WU
;
Shengyun DAI
;
Ruichao LIN
;
Chongjun ZHAO
Author Information
1. Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica,School of Chinese Materia Medica,Beijing University of Chinese Medicine,Beijing,100029,China
- Keywords:
Polyphyllin Ⅰ;
Polyphyllin Ⅱ;
Zebrafish;
Hepatotoxicity;
SQLE
- From:
Journal of Pharmaceutical Analysis
2023;13(1):39-54
- CountryChina
- Language:Chinese
-
Abstract:
Polyphyllin Ⅰ(PPⅠ)and polyphyllin Ⅱ(PⅡ)are the main active substances in the Paris polyphylla.However,liver toxicity of these compounds has impeded their clinical application and the potential hepatotoxicity mechanisms remain to be elucidated.In this work,we found that PPⅠ and PⅡ exposure could induce significant hepatotoxicity in human liver cell line L-02 and zebrafish in a dose-dependent manner.The results of the proteomic analysis in L-02 cells and transcriptome in zebrafish indicated that the hepa-totoxicity of PPⅡ and PⅡwas associated with the cholesterol biosynthetic pathway disorders,which were alleviated by the cholesterol biosynthesis inhibitor lovastatin.Additionally,3-hydroxy-3-methy-lglutaryl CoA reductase(HMGCR)and squalene epoxidase(SQLE),the two rate-limiting enzymes in the choles-terol synthesis,selected as the potential targets,were confirmed by the molecular docking,the over-expression,and knockdown of HMGCR or SQLE with siRNA.Finally,the pull-down and surface plasmon resonance technology revealed that PPⅠ could directly bind with SQLE but not with HMGCR.Collectively,these data demonstrated that PPⅠ-induced hepatotoxicity resulted from the direct binding with SQLE protein and impaired the sterol-regulatory element binding protein 2/HMGCR/SQLE/lanosterol synthase pathways,thus disturbing the cholesterol biosynthesis pathway.The findings of this research can contribute to a better understanding of the key role of SQLE as a potential target in drug-induced hepatotoxicity and provide a therapeutic strategy for the prevention of drug toxic effects with similar structures in the future.
