Ezetimibe抑制胆固醇结石形成的实验研究

Ezetimibe prevented cholesterol gallstone formation in mice fed with lithogenic diet

目的 :探讨ezetimibe(Eze)对胆囊胆固醇结石形成的抑制作用。方法 :将30只雄性成年C57BL/6小鼠随机分为普通饲料喂养(chow)组、成石饲料喂养(LD)组和成石饲料加Eze组[Eze 5 mg/(kg·d)灌胃]。饲养8周后收集血清、肝脏、小肠和胆囊。观察胆囊内胆固醇结石形成情况。采用酶法测定血清、胆汁成分、肝组织胆固醇含量。采用实时定量PCR测定肝脏和小肠胆固醇代谢相关基因mRNA相对表达量。结果:chow组小鼠胆囊内未发现结石形成。LD组小鼠胆囊结石形成率为100%。Eze组完全无结石形成。Eze组小鼠小肠胆固醇吸收率(9.29%±4.32%),较LD组(58.62%±3.10%)和chow组(56.42%±2.67%)均显著降低(P<0.01)。LD组血清胆固醇[(4.99±0.50)mmol/L]和肝组织胆固醇含量[(22.92±2.39)mg/g]均较chow组[(2.87±0.06)mmol/L和(2.45±0.08)mg/g]显著增加(P<0.05)。Eze组血清胆固醇[(1.11±0.10)mmol/L]和肝组织胆固醇含量[(2.70±0.07)mg/g]均较LD组显著降低(P<0.05)。LD组小鼠胆汁胆固醇含量[LD组(10.87±1.46)mmol/L比chow组(3.67±0.58)mmol/L]和胆固醇饱和指数[LD组(1.42±0.19)比chow组(0.59±0.02)]显著增加。Eze组胆汁胆固醇含量[(2.72±0.29)mmol/L]和胆固醇饱和指数(0.57±0.07)均较LD组显著降低(P<0.01)。结论:Eze抑制小肠胆固醇肠道摄取,具有预防胆囊胆固醇结石形成的作用。

Objective To investigate the effect of prevention on cholesterol gallstone formation by ezetimibe （Eze） in mice. Methods Thirty adult male C57BL/6 mice were randomly divided into three groups, fed with chow diet （chow group）, lithogenie diet （LD group） and lithogenic diet with 5 mg/ （kg@ d） ezetimibe by oral garage （Eze group） for 8 weeks. On sacrifice, occurrence of gallstone was observed. Serum, liver, intestine and gallbladder were collected from each mouse. The serum lipids, hepatic cholesterol and biliary lipid composition were quantified by enzymatic methods. Expression of genes involved in metabolism of cholesterol in liver and intestines were measured by real-time quantitative PCR. Results No gallstone was observed in chow group. All mice formed gallstone in LD group （100%）. No gallstone was formed in Eze group also. The intestinal cholesterol absorption rate in Eze group （9.29%±4.32%） significantly reduced when compared with LD group （58.62%±3.10%） and chow group （56.42%±2.67%） （P〈0.01）. Serum cholesterol level and hepatic cholesterol level in LD group [（4.99±0.50） mmol/L and （22.92±2.39） mg/g] increased markedly compared with chow group [（2.87±0.06） mmol/L and （2.45±0.08） mg/g] （P〈0.05）. Eze group lowered both serum cholesterol level [（1.11±0.10） mmol/L] and hepatic cholesterol level [（2.70±0.07） mg/g] compared with LD group （P〈0.05）. LD group has significantly higher biliary cholesterol content [LD group （10.87±1.46） mmol/L vs chow group （3.67±0.58） mmol/L] and cholesterol saturation index （CSI） [LD group：（1.42±0.19） vs chow group： （0.59±0.02）]. Biliary cholesterol content [（2.72±0.29） mmol/L] and CSI （0.57 ±0.07） in Eze group decreased markedly compared with LD group （P〈0.01）. Conclusions Eze could prevent cholesterol gallstone formation in mice through inhibition of intestinal cholesterol absorption.