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Fig. 2





Dose-dependent inhibition of incorporation of [14C]acetate into cholesterol by taxifolin. Confluent, monolayer HepG2 cell cultures were supplemented with various concentrations of taxifolin in SF-RPMI for 18 h. Untreated control cells received 0.1% (v/v) ethanol without taxifolin. Incubations were continued for 6 h in the presence of [14C]acetate (5 μCi/ml). Total cellular cholesterol was then determined by TLC and scintillation counting. Data are expressed as percent incorporation (mean ± SD) of [14C]acetate into cholesterol of duplicate samples repeated in three separate experiments. * P < 0.05 versus control.

Secretion of cholesterol into the culture medium was also analyzed simultaneously in cells treated with and without 200 μM taxifolin. Results showed a response similar to that observed intracellularly. Taxifolin significantly inhibited the secretion of free cholesterol and CE by 81 ± 1 and 80 ± 5%, respectively (P < 0.05, n = 3). Together, the data suggest that the taxifolin-induced inhibition of cholesterol synthesis resulted in a concomitant decrease in its secretion (summarized in Fig. 4).

Taxifolin suppresses HMG-CoA reductase activity and CE formation

To determine the underlying mechanism of action of taxifolin on cholesterol synthesis, HMGR activity was measured by the rate of incorporation of [14C]HMG-CoA into mevalonate in permeabilized cells. This method has been described previously and has been used to study factors that modulate HMGR activity (13, 17). It uses digitonin, which selectively permeabilized the plasma membrane, leaving the endoplasmic reticulum (ER) morphologically intact and functional. As shown in Fig. 3, taxifolin (200 μM, 24 h) reduced HMGR activity by 47 ± 7% (P < 0.05, n = 3). This result suggest that taxifolin produces its cholesterol-lowering effect through the inhibition of HMGR, the rate-limiting enzyme in cholesterol biosynthesis.

To examine further the effect of taxifolin on CE formation, cholesterol esterification was determined in situ by the rate of incorporation of [14C]oleic acid into cellular CE. As shown in Fig. 3, taxifolin (200 μM, 24 h) reduced cholesterol esterification by 53 ± 2% (P < 0.05, n = 3), suggesting that taxifolin may also limit ACAT activity. However, we cannot rule out the possibility that the decreased HMGR activity observed may have led to a decrease in esterified cholesterol due to lower levels of substrate.

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Date: 2015-09-18; view: 201; Нарушение авторских прав; Помощь в написании работы --> СЮДА...



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