Potential Mechanism of S. baicalensis on Lipid Metabolism Explored via Network Pharmacology and Untargeted Lipidomics

Abstract

Background

S. baicalensis, a traditional herb, has great potential in treating diseases associated with aberrant lipid metabolism, such as inflammation, hyperlipidemia, atherosclerosis and Alzheimer’s disease.

Aim of the Study

To elucidate the mechanism by which S. baicalensis modulates lipid metabolism and explore the medicinal effects of S. baicalensis at a holistic level.

Materials and Methods

The potential active ingredients of S. baicalensis and targets involved in regulating lipid metabolism were identified using a network pharmacology approach. Metabolomics was utilized to compare lipids that were altered after S. baicalensis treatment in order to identify significantly altered metabolites, and crucial targets and compounds were validated by molecular docking.

Results

Steroid biosynthesis, sphingolipid metabolism, the PPAR signaling pathway and glycerolipid metabolism were enriched and predicted to be potential pathways upon which S. baicalensis acts. Further metabolomics assays revealed 14 significantly different metabolites were identified as lipid metabolism-associated elements. After the pathway enrichment analysis of the metabolites, cholesterol metabolism and sphingolipid metabolism were identified as the most relevant pathways. Based on the results of the pathway analysis, sphingolipid and cholesterol biosynthesis and glycerophospholipid metabolism were regarded as key pathways in which S. baicalensis is involved to regulate lipid metabolism.

Conclusion

According to our metabolomics results, S. baicalensis may exert its therapeutic effects by regulating the cholesterol biosynthesis and sphingolipid metabolism pathways. Upon further analysis of the altered metabolites in certain pathways, agents downstream of squalene were significantly upregulated; however, the substrate of SQLE was surprisingly increased. By combining evidence from molecular docking, we speculated that baicalin, a major ingredient of S. baicalensis, may suppress cholesterol biosynthesis by inhibiting SQLE and LSS, which are important enzymes in the cholesterol biosynthesis pathway. In summary, this study provides new insights into the therapeutic effects of S. baicalensis on lipid metabolism using network pharmacology and lipidomics.

Keywords:

• S. baicalensis
• network pharmacology
• cortex metabolomics
• lipid metabolism
• molecular docking

Acknowledgments

This study was financially supported by the National Natural Science Foundation of China (Project Nos. 81873027 and 81573635), the Qing-Lan Project of Jiangsu Province, the Open Project Program of Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica (No. JKLPSE201820), the Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), the Project of the Innovation Research Team of Nanjing University of Chinese Medicine, and the Project Funded by the Six Talent Project in Jiangsu Province.

Abbreviations

PPARs, peroxisome proliferator-activated receptor; SQLE, squalene monooxygenase; LSS, lanosterol synthase; BBB, bblood-brainbarrier; TCM, traditional Chinese medicine; OB, oral bioavailability; DL, drug-likeness; HPLC, high-performance liquid chromatography; GO, Gene Ontology; BP, biological processes; CC, cellular components; MF, molecular functions; KEGG, Kyoto Encyclopedia of Genes and Genomes; PPI, pprotein–proteininteraction; PCA, principal component analysis; PLSDA, partial lleast-squaresdiscrimination analysis; LacCer, lactosylceramide; GlcCer, glucosylceramide; CE, cholesterol ester; TG, triacylglycerol; SM, sphingomyelin; SOAT, sterol O-acyltransferase; CPT1A, carnitine O-palmitoyltransferase 1, liver isoform; SMPD1, sphingomyelin phosphodiesterase; TYR, tyrosinase; GLY, glycine; CYS, cysteine; PHE, phenylalanine; ILE, isoleucine; VAL, valine; LEU, leucine; PRO, proline.

Disclosure

The authors reported no conflicts of interest for this work and declare that the study was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.