The cholecystokinin-1 receptor antagonist devazepide increases cholesterol cholelithogenesis in mice.
The cholecystokinin-1 receptor antagonist devazepide increases cholesterol cholelithogenesis in mice.
复制标题
胆囊收缩素-1 受体拮抗剂 devazepide 可增加小鼠体内胆固醇胆石生成。
DOI：
10.1111/eci.12580
复制
发表时间：
2016
影响因子：
5.5
通讯作者：
Wang,DavidQ-H
中科院分区：
文献类型：
--
作者：
Wang,HelenH;Portincasa,Piero;Wang,DavidQ-H
背景胆囊收缩功能的缺陷在胆囊结石的发病中起重要作用。胆囊收缩素-1受体（CCK-1 R）拮抗剂已在动物研究和临床试验中广泛研究其对胃肠道和代谢性疾病的治疗作用。为了研究CCK-1 R拮抗剂是否能增强胆石形成，我们研究了胆固醇结晶、胆石形成、肝脏脂质分泌、灌胃地伐他汀对雄性C57 BL/6 J小鼠胆囊排空功能和肠道胆固醇吸收的影响（4 mg/天/kg）或溶剂结果在21天的喂养过程中，口服地伐他汀显著加速了胆固醇结晶和晶体生长成微结石，40%的小鼠形成胆结石，而在接受赋形剂的小鼠中仅发现聚集的胆固醇一水合物晶体。与溶剂组相比，在胆结石形成期间，地瓦昔派组中响应于高脂餐的空腹和餐后残余胆囊体积显著更大，显示胆囊排空减少和胆汁淤积。此外，devazepide显着增加胆汁胆固醇的肝脏分泌，但不是磷脂或胆汁盐。在接受devazepide治疗的小鼠中，肠道胆固醇吸收百分比较高，增加了肝脏中乳糜微粒衍生胆固醇的生物利用度，使胆汁过度分泌到胆汁中。这些异常诱导过饱和的胆汁和快速胆固醇crystallization.ConclusionsThe有效的CCK-1 R拮抗剂devazepide通过损害胆囊排空功能，破坏胆汁胆固醇代谢和增强肠道胆固醇吸收增加对胆石形成的易感性在小鼠中。
BackgroundA defect in gallbladder contraction function plays a key role in the pathogenesis of gallstones. The cholecystokinin‐1 receptor (CCK‐1R) antagonists have been extensively investigated for their therapeutic effects on gastrointestinal and metabolic diseases in animal studies and clinical trials. However, it is still unknown whether they have a potential effect on gallstone formation.DesignTo study whether the CCK‐1R antagonists enhance cholelithogenesis, we investigated cholesterol crystallization, gallstone formation, hepatic lipid secretion, gallbladder emptying function and intestinal cholesterol absorption in male C57BL/6J mice treated by gavage with devazepide (4 mg/day/kg) or vehicle (as controls) twice per day and fed the lithogenic diet for 21 days.ResultsDuring 21 days of feeding, oral administration of devazepide significantly accelerated cholesterol crystallization and crystal growth to microlithiasis, with 40% of mice forming gallstones, whereas only agglomerated cholesterol monohydrate crystals were found in mice receiving vehicle. Compared to the vehicle group, fasting and postprandial residual gallbladder volumes in response to the high‐fat meal were significantly larger in the devazepide group during cholelithogenesis, showing reduced gallbladder emptying and bile stasis. Moreover, devazepide significantly increased hepatic secretion of biliary cholesterol, but not phospholipids or bile salts. The percentage of intestinal cholesterol absorption was higher in devazepide‐treated mice, increasing the bioavailability of chylomicron‐derived cholesterol in the liver for biliary hypersecretion into bile. These abnormalities induced supersaturated bile and rapid cholesterol crystallization.ConclusionsThe potent CCK‐1R antagonist devazepide increases susceptibility to gallstone formation by impairing gallbladder emptying function, disrupting biliary cholesterol metabolism and enhancing intestinal cholesterol absorption in mice.