The interaction between polyphyllin I and SQLE protein induces hepatotoxicity through SREBP-2/HMGCR/SQLE/LSS pathway

Zhiqi Li; Qiqi Fan; Meilin Chen; Ying Dong; Farong Li; Mingshuang Wang; Yulin Gu; Simin Guo; Xianwen Ye; Jiarui Wu; Shengyun Dai; Ruichao Lin; Chongjun Zhao

doi:10.1016/j.jpha.2022.11.005

Volume 13 Issue 1

Jan. 2023

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Article Navigation > Journal of Pharmaceutical Analysis > 2023 > 13(1): 39-54

Zhiqi Li, Qiqi Fan, Meilin Chen, Ying Dong, Farong Li, Mingshuang Wang, Yulin Gu, Simin Guo, Xianwen Ye, Jiarui Wu, Shengyun Dai, Ruichao Lin, Chongjun Zhao. The interaction between polyphyllin I and SQLE protein induces hepatotoxicity through SREBP-2/HMGCR/SQLE/LSS pathway[J]. Journal of Pharmaceutical Analysis, 2023, 13(1): 39-54. doi: 10.1016/j.jpha.2022.11.005

Citation:

Zhiqi Li, Qiqi Fan, Meilin Chen, Ying Dong, Farong Li, Mingshuang Wang, Yulin Gu, Simin Guo, Xianwen Ye, Jiarui Wu, Shengyun Dai, Ruichao Lin, Chongjun Zhao. The interaction between polyphyllin I and SQLE protein induces hepatotoxicity through SREBP-2/HMGCR/SQLE/LSS pathway[J]. Journal of Pharmaceutical Analysis, 2023, 13(1): 39-54. doi: 10.1016/j.jpha.2022.11.005

Citation:

Zhiqi Li, Qiqi Fan, Meilin Chen, Ying Dong, Farong Li, Mingshuang Wang, Yulin Gu, Simin Guo, Xianwen Ye, Jiarui Wu, Shengyun Dai, Ruichao Lin, Chongjun Zhao. The interaction between polyphyllin I and SQLE protein induces hepatotoxicity through SREBP-2/HMGCR/SQLE/LSS pathway[J]. Journal of Pharmaceutical Analysis, 2023, 13(1): 39-54. doi: 10.1016/j.jpha.2022.11.005

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The interaction between polyphyllin I and SQLE protein induces hepatotoxicity through SREBP-2/HMGCR/SQLE/LSS pathway

doi: 10.1016/j.jpha.2022.11.005

a. Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China;
b. Key Laboratory of Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, Shaanxi Normal University, Xi'an, 710119, China;
c. National Institutes for Food and Drug Control, Beijing, 102629, China

Funds:

We are grateful to the Beijing Key Laboratory of Traditional Chinese Medicine Quality Evaluation for providing experimental instruments and equipment. We thank Beijing University of Chinese Medicine for providing the laboratory platform. The authors would like to express their gratitude to Edit Springs (https://www.editsprings.cn/) for the expert linguistic services provided. This work was supported by the National Natural Science Foundation of China (Grant No.: 82204753), the Scientific Research Staring Foundation for the New Teachers of Beijing University of Chinese Medicine (Grant No.: 2020-JYB-XJSJJ-009), and Special Scientific Research for Traditional Chinese Medicine of State Administration of Traditional Chinese Medicine of China (Grant No.: 201507004). The funders had no role in the study design, data collection, data analysis, interpretation, or writing of the report.

Received Date: Jun. 05, 2022
Accepted Date: Nov. 12, 2022
Rev Recd Date: Nov. 10, 2022
Publish Date: Nov. 19, 2022

Abstract

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 hepatotoxicity of PPI and PII was 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 cholesterol synthesis, selected as the potential targets, were confirmed by the molecular docking, the overexpression, 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.
- Polyphyllin I,
- Polyphyllin Ⅱ,
- Zebrafish,
- Hepatotoxicity,
- SQLE

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References

Z. Liu, W. Gao, S. Man, et al., Pharmacological evaluation of sedative-hypnotic activity and gastro-intestinal toxicity of Rhizoma Paridis saponins, J. Ethnopharmacol. 144 (2012) 67-72

S. Man, P. Qiu, J. Li, et al., Global metabolic profiling for the study of Rhizoma Paridis saponins-induced hepatotoxicity in rats, Environ. Toxicol. 32 (2017) 99-108

Z. Jia, C. Zhao, M. Wang, et al., Hepatotoxicity assessment of Rhizoma Paridis in adult zebrafish through proteomes and metabolome, Biomed. Pharmacother. 121 (2020), 109558

C. Zhao, M. Wang, J. Huang, et al., Integrative analysis of proteomic and metabonomics data for identification of pathways related to Rhizoma Paridis-induced hepatotoxicity, Sci. Rep. 10 (2020), 6540

M. Chen, K. Ye, B. Zhang, et al., Paris Saponin Ⅱ inhibits colorectal carcinogenesis by regulating mitochondrial fission and NF-κB pathway, Pharmacol. Res. 139 (2019) 273-285

J. He, S. Yu, C. Guo, et al., Polyphyllin I induces autophagy and cell cycle arrest via inhibiting PDK1/Akt/mTOR signal and downregulating cyclin B1 in human gastric carcinoma HGC-27 cells, Biomed. Pharma. 117 (2019), 109189

W.P. Wang, Y. Liu, M.Y. Sun, et al., Hepatocellular toxicity of Paris saponins I, Ⅱ, VI and VⅡ on two kinds of hepatocytes-HL-7702 and HepaRG cells, and the underlying mechanisms, Cells 8 (2019), 690

W. Wang, X. Dong, L. You, et al., Apoptosis in HepaRG and HL-7702 cells inducted by polyphyllin Ⅱ through caspases activation and cell-cycle arrest, J. Cell. Physiol. 234 (2019) 7078-7089

M.L. Cowan, T.M. Rahman, S. Krishna, Proteomic approaches in the search for biomarkers of liver fibrosis, Trends Mol. Med. 16 (2010) 171-183

L.A. Liotta, M. Ferrari, E. Petricoin, Clinical proteomics: written in blood, Nature 425 (2003), 905

Q. Gao, H. Zhu, L. Dong, et al., Integrated proteogenomic characterization of HBV-related hepatocellular carcinoma, Cell 179 (2019), 1240

B.F. Cravatt, G.M. Simonm J.R. Yates 3rd, The biological impact of mass-spectrometry-based proteomics, Nature 450 (2007) 991-1000

Y. Zhang, X. Wang, C. Chen, et al., Regulation of TBBPA-induced oxidative stress on mitochondrial apoptosis in L02 cells through the Nrf2 signaling pathway, Chemosphere 226 (2019) 463-471

Y. Li, Y. Song, M. Zhao, et al., A novel role for CRTC2 in hepatic cholesterol synthesis through SREBP-2, Hepatology 66 (2017) 481-497

K.W. Lee, N.J. Kang, Y.S. Heo, et al., Raf and MEK protein kinases are direct molecular targets for the chemopreventive effect of quercetin, a major flavonol in red wine, Cancer Res. 68 (2008) 946-955

Y. Liang, L. Yi, P. Deng, et al., Rapamycin antagonizes cadmium-induced breast cancer cell proliferation and metastasis through directly modulating ACSS2, Ecotoxicol. Environ. Saf. 224 (2021),112626

C. Zhao, M. Wang, Z. Jia, et al., Similar hepatotoxicity response induced by Rhizoma Paridis in zebrafish larvae, cell and rat, J. Ethnopharmacol. 250 (2020), 112440

Z. Li, Y. Tang, Z. Liu, et al., Hepatotoxicity induced by PPⅥ and PPⅦ in zebrafish were related to the Cholesterol disorder, Phytomedicine 95 (2022), 153787.

S. Lecomte, D. Habauzit, T.D. Charlier, et al., Emerging estrogenic pollutants in the aquatic environment and breast cancer, Genes 8 (2017),229

H. Ebrahimi, M. Naderian, A.A. Sohrabpour, New concepts on pathogenesis and diagnosis of liver fibrosis; A review article, Middle East J. Dig. Dis. 8 (2016) 166-178

M.F. Smeland, C. McClenaghan, H.I. Roessler, et al., ABCC9-related Intellectual disability Myopathy Syndrome is a KATP channelopathy with loss-of-function mutations in ABCC9, Nat. Commun. 10 (2019), 4457

C. Li, M. Wang, T. Fu, et al., Lipidomics indicates the hepatotoxicity effects of EtOAc extract of Rhizoma Paridis, Front. Pharmacol. 13 (2022), 799512.

T. Zhang, S. Zhong, T. Li, et al., Saponins as modulators of nuclear receptors, Crit. Rev. Food Sci. Nutr. 60 (2020) 94-107

M. Robles-Diaz, A. Gonzalez-Jimenez, I. Medina-Caliz, et al., Distinct phenotype of hepatotoxicity associated with illicit use of anabolic androgenic steroids, Aliment. Pharmacol. Ther. 41 (2015) 116-125

F.R. Maxfield, G. van Meer, Cholesterol, the central lipid of mammalian cells, Curr. Opin. Cell Biol. 22 (2010) 422-429

K.E. Brett, Z.M. Ferraro, J. Yockell-Lelievre, et al., Maternal-fetal nutrient transport in pregnancy pathologies: the role of the placenta, Int. J. Mol. Sci. 15 (2014) 16153-16185

Y. Zhang, S.R. Breevoort, J. Angdisen, et al., Liver LXRα expression is crucial for whole body cholesterol homeostasis and reverse cholesterol transport in mice, J. Clin. Invest. 122 (2012) 1688-1699

J. Luo, H. Yang, B.-L. Song, Mechanisms and regulation of cholesterol homeostasis, Nat. Rev. Mol. Cell Biol. 21 (2020) 225-245

T. Rezen, The impact of cholesterol and its metabolites on drug metabolism, Expet Opin. Drug Metabol. Toxicol. 7 (2011) 387-398

M. Tan, J. Ye, M. Zhao, et al., Recent developments in the regulation of cholesterol transport by natural molecules, Phytother Res. 35 (2021) 5623-5633

D. Xu, Z. Wang, Y. Zhang, et al., PAQR3 modulates cholesterol homeostasis by anchoring Scap/SREBP complex to the Golgi apparatus, Nat. Commun. 6 (2015), 8100

A.K. Groen, V.W. Bloks, H. Verkade, et al., Cross-talk between liver and intestine in control of cholesterol and energy homeostasis, Mol. Aspect. Med. 37 (2014) 77-88

M. Vinaixa, M.A. Rodriguez, A. Rull, et al., Metabolomic assessment of the effect of dietary cholesterol in the progressive development of fatty liver disease, J. Proteome Res. 9 (2010) 2527-2538

Y. Jo, P.C. Lee, P.V. Sguigna, et al., Sterol-induced degradation of HMG CoA reductase depends on interplay of two Insigs and two ubiquitin ligases, gp78 and Trc8, Proc. Natl. Acad. Sci. U. S. A. 108 (2011) 20503-20508

Y. Zhu, S.Q. Kim, Y. Zhang, et al., Pharmacological inhibition of acyl-coenzyme A: Cholesterol acyltransferase alleviates obesity and insulin resistance in diet-induced obese mice by regulating food intake, Metabolism 123 (2021), 154861.

F.-J. Liao, P.-F. Zheng, Y.-Z. Guan, et al., Weighted gene co-expression network analysis to identify key modules and hub genes related to hyperlipidaemia, Nutr. Metab. 18 (2021), 24

T.-F. Liu, J.-J. Tang, P.-S. Li, et al., Ablation of gp78 in liver improves hyperlipidemia and insulin resistance by inhibiting SREBP to decrease lipid biosynthesis, Cell Metabol. 16 (2012) 213-225

U. Haas, E. Raschperger, M. Hamberg, et al., Targeted knock-down of a structurally atypical zebrafish 12S-lipoxygenase leads to severe impairment of embryonic development, Proc. Natl. Acad. Sci. U. S. A. 108 (2011) 20479-20484

Z. Hubler, R.M. Friedrich, J.L. Sax, et al., Modulation of lanosterol synthase drives 24,25-epoxysterol synthesis and oligodendrocyte formation, Cell Chem. Biol. 28 (2021) 866-875.e5

A.T. Cohain, W.T. Barrington, D.M. Jordan, et al., An integrative multiomic network model links lipid metabolism to glucose regulation in coronary artery disease, Nat. Commun. 12 (2021), 547

I. Renard, M. Grandmougin, A. Roux, et al., Small-molecule affinity capture of DNA/RNA quadruplexes and their identification in vitro and in vivo through the G4RP protocol, Nucleic Acids Res. 47 (2019) 5502-5510

X. Chi, X. Liu, C. Wang, et al., Humanized single domain antibodies neutralize SARS-CoV-2 by targeting the spike receptor binding domain, Nat. Commun. 11 (2020), 4528

S. Ye, W. Luo, Z.A. Khan, et al., Celastrol attenuates angiotensin Ⅱ-induced cardiac remodeling by targeting STAT3, Circ. Res. 126 (2020) 1007-1023

Z. Hong, T. Liu, L. Wan, et al., Targeting squalene epoxidase interrupts homologous recombination via the ER stress response and promotes radiotherapy efficacy, Cancer Res. 82 (2022) 1298-1312

C. Li, Y. Wang, D. Liu, et al., Squalene epoxidase drives cancer cell proliferation and promotes gut dysbiosis to accelerate colorectal carcinogenesis, Gut 71 (2022) 2253-2265

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