Effect of hydrophilic phytosterol glycosyl derivatives on lipid digestion and cholesterol precipitation during in vitro dynamic gastrointestinal digestion.

Hydrophilic phytosterol derivatives are synthetic analogs of phytosterols conjugated with hydrophilic moieties, designed to enhance water solubility and bioaccessibility compared to free phytosterols. The interactive effect of these derivatives on lipid digestion and cholesterol precipitation remains unclear. Building on our prior synthesis of a homologous series of hydrophilic phytosterol glycosyl derivatives, this study employed an in vitro dynamic human stomach-intestine system IV (DHSI-IV) to elucidate the effect of free phytosterols and phytosterol glycosyl derivatives on these two closely linked processes. Results showed that neither free phytosterols nor phytosterol glycosyl derivatives promoted cholesterol precipitation by inhibiting lipid digestion. Notably, phytosterol glycosyl derivatives significantly enhanced triglyceride hydrolysis. Furthermore, free phytosterols and phytosterol glycosyl derivatives exhibited distinctly different mechanisms of action in mediating cholesterol precipitation. Specifically, free phytosterols targeted cholesterol directly, promoting its precipitation through a co-precipitation mechanism. Conversely, phytosterol glycosyl derivatives altered the properties of digesta by increasing particle size and reducing surface electronegativity. This induced flocculation, causing the cholesterol-loaded micelles to be removed from the micellar phase and ultimately promoting cholesterol precipitation. These findings provide new insights into the cholesterol-lowering potential of hydrophilic phytosterol derivatives and contribute to the development of cholesterol-absorption inhibitors.