Basic—Liver, Pancreas, and Biliary TractEffect of Ezetimibe on the Prevention and Dissolution of Cholesterol Gallstones
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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.