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Our previous study has shown that a soluble hesperidin derivative, glucosyl hesperidin (G-hesperidin), preferentially lowers serum triglyceride (TG) level in hypertriglyceridemic subjects through the improvement of very low-density lipoprotein (VLDL) metabolic abnormality. G-Hesperidin has also been found to decrease an elevated serum apolipoprotein B (apo B) level in the hypertriglyceridemic subjects, suggesting a possibility that this compound suppresses excess VLDL secretion in the liver. In the present study, to gain a better understanding of possible mechanisms by which G-hesperidin lowers serum TG, we examined whether this derivative affects apo B secretion from HepG2 human hepatoma cells, a model of hepatic VLDL secretion. As a result, G-hesperidin significantly reduced apo B secretion from the oleate-stimulated HepG2 cells. Furthermore, G-hesperidin significantly suppressed apo B secretion only in the oleate-stimulated cells and failed to act on the cells incubated without oleate. In the oleate-stimulated cells, G-hesperidin significantly decreased cellular cholesteryl ester (CE), although it had no effect on cellular TG or free cholesterol amounts. Moreover, the oleate-stimulated cells had a decrease in cellular apo B amounts by G-hesperidin exposure. These findings indicate that G-hesperidin down-regulates the assembly of apo B-containing lipoproteins via the reduction of CE synthesis augmented with oleate and results in suppressing excess apo B secretion from the cells. This effect is speculated to be associated with the improvement of VLDL metabolic abnormality in hypertriglyceridemic subjects and considered as a mechanism of lowering serum TG.

Although hesperidin lowers serum total cholesterol (TC) or triglyceride (TG) in animal models, its effect in humans remains unclear. Using a soluble hesperidin derivative, glucosyl hesperidin (G-hesperidin), as a hesperidin source, we examined the efficacy on hyperlipidemic subjects. G-Hesperidin was administered to the subjects at 100 or 500 mg/d for 6 wk. The percentage of subjects who had a change in serum cholesterol levels was less than 20%. However, 45-55% of the total subjects showed a reduction in serum TG level. The subjects were classified into normal (TC230mg/dL, TG150mg/dL), high-TC (TC230 mg/dL, TG150 mg/dL) and high-TG (TG150 mg/dL) types. While serum cholesterol levels scarcely changed in any phenotype, TG level was significantly reduced by administration in the high-TG type. In this phenotype, serum apolipoprotein (apo) C-II and E levels decreased by the administration, but non-apo B. G-Hesperidin also raised low-density lipoprotein (LDL)-cholesterol/apo B in the high-TG type. These results indicate that G-hesperidin preferentially lowers serum TG in hypertriglyceridemic subjects and that this effect is possibly caused by the facilitation of catabolism of TG-rich lipoproteins and may contribute to the reduction of small dense LDL.