Dioscin attenuates hyperlipidemia by dual modulation of intestinal triglyceride and cholesterol absorption.

Dioscin, a natural steroidal saponin derived from Dioscorea species, has been reported to exhibit lipid-lowering activity despite its extremely low oral bioavailability. This study aimed to elucidate whether dioscin exerts its lipid-lowering effects through intestinal mechanisms. Using both high-fat diet (HFD)-induced and acute lipid-challenge rat models, dioscin significantly reduced plasma triglyceride (TG) and total cholesterol (TC) levels, indicating an inhibitory effect on intestinal lipid absorption. In vitro assays demonstrated that dioscin inhibited pancreatic triglyceride lipase (PTL) activity with moderate potency and suppressed Niemann-Pick C1-Like 1 (NPC1L1)-mediated cholesterol uptake in Caco-2 cells. Surface plasmon resonance (SPR) analysis and molecular docking suggested direct interactions between dioscin and both PTL and NPC1L1, suggesting that dioscin interferes with intestinal lipid absorption through mechanisms involving TG hydrolysis and cholesterol transport. These findings provide mechanistic insight into the intestinal lipid-lowering activity of dioscin and highlight its potential as a natural lead compound for the development of safe and intestine- restricted lipid-lowering agents.