Suppression of Apolipoprotein B Secretion from HepG2 Cells by Glucosyl Hesperidin

Abstract

SummaryOur 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 downregulates 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. Key Words glucosyl hesperidin, very low-density lipoprotein, apolipoprotein B, cholesteryl ester, HepG2 cells Hesperidin, a citrus flavonoid, is well known to decrease capillary fragility and permeability ( 1 ). This compound has also been reported to have various physiological activities including antioxidant effect ( 1 ), antihypertensive effect ( 2 ) and antiallergic effect ( 3 ). Therefore, hesperidin has attracted attention as a multifunctional food ingredient. However, the use of this flavonoid in the field of foods has been limited because of its low water solubility.To solve this problem, Hijiya and Miyake have synthesized a soluble derivative of hesperidin, glucosyl hesperidin (G-hesperidin), by regioselective transglycosylation with cyclodextrin glucanotransferase from Bacillus stearothermophilus (Fig. 1) ( 4 ). G-Hesperidin is very soluble in water, and its solubility is about 10,000 times greater than that of conventional hesperidin ( 4 ). Moreover, it has been verified that this derivative releases hesperidin through hydrolysis by brush border ␣ -glucosidases ( 4 , 5 ). Our recent studies have shown that Ghesperidin as well as hesperidin exhibits such physiological activities as decrease of serum lipid peroxide level in hyperlipidemic mice ( 6 ), antihypertensive effect on spontaneously hypertensive rats ( 7 , 8 ) and suppression of passive ...

A Combination of Glucosyl Hesperidin and Caffeine Exhibits an Anti-obesity Effect by Inhibition of Hepatic Lipogenesis in Mice

“…In such experimental conditions, a plasma TG‐lowering effect has been shown to be exerted by increasing TG clearance but not by inhibiting lipogenesis in the liver (Murosaki et al ., ). Therefore, effects of G‐hesperidin alone or G‐hesperidin + caffeine, which could suppress VLDL secretion from the liver (Miwa et al ., ), on plasma TG levels may not appear in the present study.…”

“…In such experimental conditions, a plasma TG-lowering effect has been shown to be exerted by increasing TG clearance but not by inhibiting lipogenesis in the liver (Murosaki et al, 2007). Therefore, effects of G-hesperidin alone or G-hesperidin + caffeine, which could suppress VLDL secretion from the liver (Miwa et al, 2006), on plasma TG levels may not appear in the present study. DNA microarray analysis revealed that apoAI and apoAII were markedly decreased in epididymal adipose tissue in obese KK mice fed a low-fat diet that included G-hesperidin + caffeine (Table 4).…”

“…Recent studies indicate that G-hesperidin acts to reduce serum TG in several animal models (Akiyama et al, 2009;Chiba et al, 2003;Mitsuzumi et al, 2011) and hypertriglyceridemic subjects (Miwa et al, 2005;Miwa et al, 2004). The mechanism of its TG-lowering effect has been reported to be downregulation of synthesis/secretion of very-low-density lipoprotein (VLDL) (Miwa et al, 2006). It has also been shown that the TG-lowering effect might be attributable to reduced hepatic TG contents through its inhibition of lipogenesis and its induction of fatty acid beta-oxidation in high-fat diet-fed rats (Mitsuzumi et al, 2011).…”

Lemon Polyphenols Suppress Diet-induced Obesity by Up-Regulation of mRNA Levels of the Enzymes Involved in β-Oxidation in Mouse White Adipose Tissue

“…f.) have been reported to be such flavanone glycosides as eriocitrin (eriodictyol 7- O -β-rutinoside) and hesperidin (hesperetin 7- O -β-rutinoside), naringin (naringenine-7-rhamnosidoglucoside), and such flanone glycosides as diosmin (diosmetin 7- O -β-rutinoside) and 6,8 C-diglucosyldiosmetin [ 9 , 10 ], all of which are supposed to have a number of positive health effects in the prevention of lifestyle-related diseases, and to have antiinflammatory, anticancer, and antiviral activities based on their antioxidant activity [ 11 – 14 ]. Furthermore, previous studies demonstrated the effects of these flavonoids on lipid and glucose metabolism in experimental animals and humans [ 15 – 19 ].…”

Oral intake of a combination of glucosyl hesperidin and caffeine elicits an anti-obesity effect in healthy, moderately obese subjects: a randomized double-blind placebo-controlled trial

“…G-hesperidin has been reported to reduce serum levels of triglyceride (TG) in animals [ 13 – 15 ] and subjects with hypertriglyceridemia [ 16 , 17 ]. The mechanism of the TG-lowering effect of G-hesperidin is thought to be down-regulation of the synthesis/secretion of very-low-density lipoprotein in hepatocytes [ 18 ], inhibition of lipogenesis, and induction of beta oxidation of fatty acids in high-fat diet-fed rats [ 15 ]. Studies have shown that daily intake of G-hesperidin (500 mg) in subjects with a moderately high BMI for 12 weeks decreases abdominal fat significantly during the period, but these decreases do not differ significantly from those of subjects taking a placebo [ 19 ].…”