Saikosaponins ameliorate hyperlipidemia in rats by enhancing hepatic lipid and cholesterol metabolism

Ethnopharmacological relevance: Hyperlipidemia is the systemic manifestation of abnormal lipid metabolism, characterized by elevated circulating levels of cholesterol and triglyceride and a high risk of cardiovascular events. Radii Bupleuri (RB) is a traditional Chinese herbal product used to treat liver diseases. Our previous study demonstrated that Saikosaponins (SSs), the most potent bioactive ingredients in RB, ameliorate hepatic steatosis. However, whether SSs have anti-hyperlipidemia effects and plausible underlying mechanisms remain elusive.Aim of the study: To comprehensively evaluate the lipid-lowering potential of SSs against hyperlipidemia in rats.Materials and methods: RNA sequencing and untargeted metabolomics approaches were applied to analyze the changes in the liver transcriptome and serum lipid profile in long-term high-fat diet feeding-induced hyperlip-idemia rats in response to SSs or positive drug simvastatin (SIM) intervention.Results: Our data revealed that SSs significantly alleviated HFD-induced hypertriglyceridemia and hypercho-lesterolemia. Combined with the analysis of gene ontology enrichment analysis and gene set enrichment analysis, we found that SSs remarkably repaired the unbalanced blood lipid metabolic spectrum in a dose-dependent manner by increasing the hepatic uptake of circulating fatty acids and facilitating mitochondrial respiration in fatty acid oxidation, comparable to SIM group. In addition, SSs markedly modulated cholesterol clearance by promoting intracellular cholesterol efflux, HDL remodeling, LDL particle clearance, and bile acid synthesis. SSs also efficiently protected the liver from lipid overload-related oxidative stress and lipid peroxidation, as well as substantially exaggerated inflammatory response.Conclusion: Our research not only unraveled the intricate mechanisms underlying the lipid-lowering functions of SSs but also provided novel perspectives on developing an SSs-based therapeutic strategy for the treatment of hyperlipidemia.Classification: Metabolism.

Automated summary

This study demonstrated that Saikosaponins (SSs) from traditional Chinese medicine have therapeutic effects on hyperlipidemia by reducing the levels of cholesterol and triglyceride, improving the imbalance of lipid metabolism, and reducing oxidative stress and inflammation.