Aquatic and Crop Resource Development, National Research Council of Canada, Charlottetown, PE, Canada; Department of Biomedical Sciences, University of Prince Edward Island, Charlottetown, PE, Canada.
Aquatic and Crop Resource Development, National Research Council of Canada, Charlottetown, PE, Canada; Department of Biomedical Sciences, University of Prince Edward Island, Charlottetown, PE, Canada.
Metabolism. 2014 Sep;63(9):1167-77. doi: 10.1016/j.metabol.2014.05.013. Epub 2014 Jun 4.
The objective was to determine the mechanisms of action of berberine (BBR) on cholesterol homeostasis using in vivo and in vitro models.
Male Sprague-Dawley rats were fed the AIN-93G diet (normal control) or modified AIN-93G diet containing 28% fat, 2% cholesterol and 0.5% cholic acid with treatment of 0 (atherogenic control), 50, 100, and 150 mg/kg·d of BBR, respectively by gavaging in water for 8 weeks. Cholesterol absorption rate was measured with the dual stable isotope ratio method, and plasma lipids were determined using the enzymatic methods. Gene and protein expressions of Acyl-coenzyme A:cholesterol acyltransferase-2 were analyzed in vivo and in vitro. Cholesterol micellarization, uptake and permeability were determined in vitro.
Rats on the atherogenic diet showed significantly hypercholesterolemic characteristics compared to normal control rats. Treatment with BBR in rats on the atherogenic diet reduced plasma total cholesterol and nonHDL cholesterol levels by 29%-33% and 31%-41%, respectively, with no significant differences being observed among the three doses. The fractional dietary cholesterol absorption rate was decreased by 40%-51%. Rats fed the atherogenic diet showed lower plasma triacylglycerol levels, and no changes were observed after the BBR treatment. BBR interfered with cholesterol micellarization, decreased cholesterol uptake by Caco-2 cells and permeability through Caco-2 monolayer. BBR also inhibited the gene and protein expressions of acyl-coenzyme A cholesterol acyltransferease-2 in the small intestine and Caco-2 cells.
BBR lowered blood cholesterol levels at least in part through inhibiting the intestinal absorption and further by interfering with intraluminal cholesterol micellarization and decreasing enterocyte cholesterol uptake and secretion.
本研究旨在利用体内和体外模型来确定小檗碱（BBR）对胆固醇稳态的作用机制。
雄性 Sprague-Dawley 大鼠分别用 AIN-93G 饮食（正常对照组）或含 28%脂肪、2%胆固醇和 0.5%胆酸的改良 AIN-93G 饮食喂养 8 周，同时以水灌胃给予 0（动脉粥样硬化对照组）、50、100 和 150 mg/kg·d 的 BBR。采用双稳定同位素比法测定胆固醇吸收率，用酶法测定血浆脂质。在体内和体外分析 Acyl-coenzyme A:cholesterol acyltransferase-2 的基因和蛋白表达。在体外测定胆固醇胶束化、摄取和通透性。
与正常对照组大鼠相比，动脉粥样硬化饮食组大鼠表现出明显的高胆固醇血症特征。BBR 治疗可使动脉粥样硬化饮食组大鼠的血浆总胆固醇和非高密度脂蛋白胆固醇水平分别降低 29%-33%和 31%-41%，三个剂量组之间无显著差异。膳食胆固醇的分数吸收率降低了 40%-51%。动脉粥样硬化饮食组大鼠的血浆三酰甘油水平较低，BBR 治疗后无变化。BBR 干扰胆固醇胶束化，降低 Caco-2 细胞摄取胆固醇的能力，并降低 Caco-2 单层的通透性。BBR 还抑制了小肠和 Caco-2 细胞中酰基辅酶 A 胆固醇酰基转移酶-2 的基因和蛋白表达。
BBR 降低血胆固醇水平至少部分是通过抑制肠道吸收，进一步通过干扰腔内胆固醇胶束化，减少肠上皮细胞胆固醇摄取和分泌。
