The sugar moiety in protopanaxadiol ginsenoside affects its ability to target glucocorticoid receptor to regulate lipid metabolism

[Display omitted] •The hypolipidemic ability of protopanaxadiol ginsenosides depends on the sugar moieties and CK was the strongest one.•The protopanaxadiol ginsenosides affect lipid metabolism through glucocorticoid receptor (GR).•The expression of lipid metabolism-related genes is upregulated by CK binding to GR, which dexamethasone does not possess. Ginsenosides are natural products with hydrophobic rings adorned with sugar molecules. The elucidation of the impact of ginsenosides structure on their activity is crucial for facilitating precision-oriented modifications, thereby enhancing their suitability for drug development. Here, utilizing an ob/ob mouse model, we demonstrated that as the number of sugar moiety on the protopanaxadiol-type ginsenosides decreased, the hypolipidemic potency increased, while the aglycon exhibited negligible activity. Mechanistically, we demonstrated the dependency of ginsenosides on the glucocorticoid receptor (GR) for the regulation of lipid metabolism. Interestingly, ginsenoside CK was found to promote the transcription of lipid metabolism-related genes via GR contrast to the effects of glucocorticoids, suggesting a unique mode of action. Furthermore, we observed that a reduction in the number of sugar molecules strengthened the binding affinity of ginsenosides to GR, as determined by microscale thermophoresis. These findings highlight the critical role of the sugar moiety in modulating the lipid-regulating capacity of ginsenosides, providing valuable insights for the development of these compounds as potential therapeutic agents.