外科理论与实践

外科理论与实践 >

2018 , Vol. 23 >Issue 01: 41 - 47

DOI: https://doi.org/10.16139/j.1007-9610.2018.01.010

论著

Ezetimibe抑制胆固醇结石形成的实验研究

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  • 1.上海交通大学医学院附属瑞金医院上海消化外科研究所,上海 200025;
    2.同济大学附属东方医院胆石病中心 同济大学医学院胆石病研究所,上海 201200

收稿日期: 2017-05-08

  网络出版日期: 2020-07-25

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Ezetimibe prevented cholesterol gallstone formation in mice fed with lithogenic diet

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  • 1. Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;
    2. Center of Gallbladder Disease, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 201200, China

Received date: 2017-05-08

  Online published: 2020-07-25

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摘要

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。

关键词： Ezetimibe; 胆固醇结石病; 小肠

本文引用格式

王启晗, 孙海东, 蔡劬, 胡海, 韩天权, 蒋兆彦 . Ezetimibe抑制胆固醇结石形成的实验研究[J]. 外科理论与实践, 2018 , 23(01) : 41 -47 . DOI: 10.16139/j.1007-9610.2018.01.010

Abstract

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), lithogenic diet (LD group) and lithogenic diet with 5 mg/ (kg·d) ezetimibe by oral gavage (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.

Key words： Ezetimibe; Cholesterol gallstone disease; Intestine

参考文献

[1] Gurusamy KS, Davidson BR.Gallstones[J]. BMJ,2014,348:g2669.
[2] 中华外科学会胆道外科学组. 我国胆石病十年来的变迁[J]. 中华外科杂志,1995,33(11):652-658.
[3] 陈希纲, 刘家奇. 胆石病临床流行病学调查——附8585例分析[J]. 中华普通外科杂志,2002,17(2):99-101.
[4] 蒋兆彦, 胡海, 韩天权, 等. 胆固醇的肠肝循环:肝脏和小肠在胆石形成中的作用[J]. 外科理论与实践,2017,22(3):191-194.
[5] Abraham S, Rivero HG, Erlikh IV, et al.Surgical and nonsurgical management of gallstones[J]. Am Fam Physician,2014,89(10):795-802.
[6] 蒋兆彦, 吴健, 韩天权, 等. 胆固醇结石病防治研究的再发展[J]. 外科理论与实践,2015,20(2):108-111.
[7] Jiang ZY, Jiang CY, Wang L, et al.Increased NPC1L1 and ACAT2 expression in the jejunal mucosa from Chinese gallstone patients[J]. Biochem Biophys Res Commun,2009,379(1):49-54.
[8] Jiang ZY, Parini P, Eggertsen G, et al.Increased expression of LXR alpha, ABCG5, ABCG8, and SR-BI in the liver from normolipidemic, nonobese Chinese gallstone patients[J]. J Lipid Res,2008,49(2):464-472.
[9] Altmann SW, Davis HR, Zhu L, et al.Niemann-Pick C1 like 1 protein is critical for intestinal cholesterol absorption[J]. Science,2004,303(5661):1201-1204.
[10] Wang HH, Portincasa P, de Bari O, et al. Prevention of cholesterol gallstones by inhibiting hepatic biosynthesis and intestinal absorption of cholesterol[J]. Eur J Clin Invest,2013,43(4):413-426.
[11] Carey MC.Critical tables for calculating the cholesterol saturation of native bile[J]. J Lipid Res,1978,19(8):945-955.
[12] Garcia-Calvo M, Lisnock J, Bull HG, et al.The target of ezetimibe is Niemann-Pick C1-like 1 (NPC1L1)[J]. Proc Natl Acad Sci U S A,2005,102(23):8132-8137.
[13] Xie C, Zhou ZS, Li N, et al.Ezetimibe blocks the internalization of NPC1L1 and cholesterol in mouse small intestine[J]. J Lipid Res,2012,53(10):2092-2101.
[14] Sudhop T, Lütjohann D, Kodal A, et al.Inhibition of intestinal cholesterol absorption by ezetimibe in humans[J]. Circulation,2002,106(15):1943-1948.
[15] Reynier MO, Montet JC, Gerolami A, et al.Comparative effects of cholic, chenodeoxycholic, and ursodeoxycholic acids on micellar solubilization and intestinal absorption of cholesterol[J]. J Lipid Res,1981,22(3):467-473.
[16] Ge L, Wang J, Qi W, et al.The cholesterol absorption inhibitor ezetimibe acts by blocking the sterol-induced internalization of NPC1L1[J]. Cell Metab,2008,7(6):508-519.
[17] Zúñiga S, Molina H, Azocar L, et al.Ezetimibe prevents cholesterol gallstone formation in mice[J]. Liver Int,2008, 28(7):935-947.
[18] Bari OD, Wang HH, Portincasa P, et al.Ezetimibe prevents the formation of estrogen-induced cholesterol gallstones in mice[J]. Eur J Clin Invest,2014,44(12):1159-1168.
[19] Yu L, Hammer RE, Lihawkins J, et al.Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion[J]. Proc Natl Acad Sci U S A,2002,99(25):16237-16242.
[20] Yu L, Jia LH, Hammer RE, et al.Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol[J]. J Clin Invest,2002,110(5):671-680.
[21] Repa JJ, Berge KE, Pomajzl C, et al.Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors alpha and beta[J]. J Biol Chem,2002,277(21):18793-18800.
[22] Brown MS, Goldstein JL.The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor[J]. Cell,1997,89(3):331-340.
[23] Fuchs M, Ivandic B, Müller O, et al.Biliary cholesterol hypersecretion in gallstone-susceptible mice is associated with hepatic up-regulation of the high-density lipoprotein receptor SRBI[J]. Hepatology,2001,33(6):1451-1459.
[24] Mardones P, Quiñones V, Amigo L, et al.Hepatic cholesterol and bile acid metabolism and intestinal cholesterol absorption in scavenger receptor class B type I-deficient mice[J]. J Lipid Res,2001,42(2):170-180.
[25] Kozarsky KF, Donahee MH, Rigotti A, et al.Overexpression of the HDL receptor SR-BI alters plasma HDL and bile cholesterol levels[J]. Nature,1997,387(6631):414-417.
[26] Kan HP, Guo WB, Tan YF, et al. Statin use and risk of gallstone disease: A meta-analysis[J]. Hepatol Res,2014-10-09 [Epub ahead of print].
[27] Suuronen S, Niskanen L, Paajanen P, et al.Declining cholecystectomy rate during the era of statin use in Finland: a population-based cohort study between 1995 and 2009[J]. Scand J Surg,2013,102(3):158-163.
[28] Bodmer M, Brauchli YB, Krähenbühl S, et al.Statin use and risk of gallstone disease followed by cholecystectomy[J]. JAMA,2009,302(18):2001-2007.
[29] 蒋兆彦, 韩天权, 张圣道. 从胆石成因研究谈胆石病预防的新策略[J]. 中华肝胆外科杂志,2011,17(9):697-700.
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