Gastroenterology

Gastroenterology

Volume 134, Issue 7, June 2008, Pages 2101-2110
Gastroenterology

Basic—Liver, Pancreas, and Biliary Tract
Effect of Ezetimibe on the Prevention and Dissolution of Cholesterol Gallstones

Presented in part at the Annual Meeting of the American Gastroenterological Association, Los Angeles, California, May 23, 2006.
https://doi.org/10.1053/j.gastro.2008.03.011Get rights and content

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 ezetimibe 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 (day 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 ezetimibe 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.

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Animals and Diets

Male C57L/J mice, 6–8 weeks old, were purchased from The Jackson Laboratory (Bar Harbor, ME). All mice were provided free access to water and normal rodent chow containing trace (<0.02%) cholesterol (Harlan Teklad F6 Rodent Diet 8664; Harlan, Madison, WI). For gallstone prevention studies, mice were divided into 5 groups (n = 20 per group), fed for 8 or 12 weeks with a lithogenic diet (1% or 2% cholesterol plus 0.5% cholic acid and 15% butter fat) supplemented with ezetimibe

Effect of Ezetimibe on Biliary Cholesterol Secretion in Mice and Human Beings

At 8 weeks on the lithogenic diet, administration of ezetimibe to mice resulted in a clear dose-dependent decrease in biliary cholesterol outputs during the first hour of biliary secretion of interrupted enterohepatic circulation (Figure 1A). Similarly, biliary phospholipid outputs were reduced significantly in a dose-dependent fashion (Figure 1B). However, hepatic outputs of biliary bile salts varied slightly and were not significantly different among 4 groups of mice (Figure 1C). We also

Discussion

Cholesterol cholelithiasis is a multifactorial disease influenced by a complex interaction of genetic and environmental factors.1, 2 In mouse studies, targeted deletion of the acyl-CoA:cholesterol acyltransferase gene 2 (Acat2) results in the lack of cholesterol ester synthesis in the small intestine. This causes a marked reduction in intestinal cholesterol absorption and complete resistance to diet-induced cholesterol gallstones.24 Furthermore, absence of expression of intestinal APO-B48, but

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    Supported in part by research grants DK54012 and DK73917 (D.Q.-H.W.) from the National Institutes of Health (US Public Health Service), FIRB 2003 RBAU01RANB002 from the Italian Ministry of University and Research, ORBA060RME and ORBA07Y0GT from the University of Bari (P.P.), and a grant from Medica Sur Clinic and Foundation (N.M.–S). P.P. was a recipient of the short-term mobility grant 2005 from the Italian National Research Council.

    Previously published in abstract form in Gastroenterology 2006;130:A85.

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