Effect of ezetimibe on the prevention and dissolution of cholesterol gallstones
Effect of ezetimibe on the prevention and dissolution of cholesterol gallstones
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DOI：
10.1053/j.gastro.2008.03.011
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发表时间：
2008-06-01
期刊：
影响因子：
29.4
通讯作者：
Wang, David Q. -H
中科院分区：
文献类型：
--
作者：
Wang, Helen H.;Portincasa, Piero;Wang, David Q. -H
背景和目标：胆固醇胆石症是发达国家中最普遍和最昂贵的消化系统疾病之一，由于采用西式饮食习惯，其发病率在亚洲国家显著增加。由于动物实验表明肠道胆固醇的高效吸收有助于胆结石的形成，我们探索了强效胆固醇吸收抑制剂依折麦布是否可以预防小鼠胆结石并促进结石溶解，以及降低人胆汁胆固醇含量。研究方法：雄性胆结石易感C57 L小鼠喂食致石饲料，同时给予0、0.8、4或8 mg/kg/天的依泽米贝，持续8或12周。通过显微镜检查胆囊胆汁和胆结石。八肽胆囊收缩素反应的胆囊排空用重量法测定。胆汁脂质输出量通过物理化学方法进行分析。胆固醇吸收效率采用粪便双同位素比值法和质量平衡法测定。在依折麦布治疗前（粘土0）和治疗后30天（20 mg/天）检查了胆结石患者与无胆结石的超重受试者胆囊胆汁的脂质变化。结果如下：依折麦布通过有效减少肠道胆固醇吸收和胆汁胆固醇分泌来预防胆结石，并通过使胆汁去饱和来保护胆囊运动功能。依折麦布治疗通过形成大量的不饱和胶束促进胆结石的溶解。此外，依折麦布可显著降低胆结石患者胆汁中胆固醇饱和度，并延缓胆固醇结晶。结论：依折麦布是一种降低胆汁胆固醇含量的新方法，是通过抑制肠道胆固醇吸收预防或治疗胆固醇结石的有前景的策略。
Background & Aims: cholesterol cholelithiasis is one of the most prevalent and most costly digestive diseases in developed countries and its incidence has increased markedly in Asian countries owing to the adoption of Western-type dietary habits. Because animal experiments showed that high efficiency of intestinal cholesterol absorption contributes to gallstone formation, we explored whether the potent cholesterol absorption inhibitor ezetimibe could prevent gallstones and promote gallstone dissolution in mice and reduce biliary cholesterol content in human beings. Methods: Male gallstone-susceptible C57L mice were fed a lithogenic diet and concomitantly administered with ezedmibe at 0, 0.8, 4, or 8 mg/kg/day for 8 or 12 weeks. Gallbladder biles and gallstones were examined by microscopy. Gallbladder emptying in response to cholecystokinin octapeptide was measured gravimetrically. Biliary lipid outputs were analyzed by physical-chemical methods. Cholesterol absorption efficiency was determined by fecal dual-isotope ratio and mass balance methods. Lipid changes in gallbladder biles of gallstone patients vs overweight subjects without gallstones were examined before (clay 0) and at 30 days after ezetimibe treatment (20 mg/day). Results: Ezetimibe prevented gallstones by effectively reducing intestinal cholesterol absorption and biliary cholesterol secretion, and protected gallbladder motility function by desaturating bile in mice. Treatment with ezedmibe promoted the dissolution of gallstones by forming an abundance of unsaturated micelles. Furthermore, ezetimibe significantly reduced biliary cholesterol saturation and retarded cholesterol crystallization in biles of patients with gallstones. Conclusions: Ezetimibe is a novel approach to reduce biliary cholesterol content and a promising strategy for preventing or treating cholesterol gallstones by inhibiting intestinal cholesterol absorption.