Ezetimibe: Its Novel Effects on the Prevention and the Treatment of Cholesterol Gallstones and Nonalcoholic Fatty Liver Disease

Figure 4

Effect of ezetimibe on the dissolution of cholesterol gallstones. (a) For gallstone dissolution experiments, mice with preexisting gallstones were fed a chow diet alone for 8 weeks, which does not result in a spontaneous dissolution of gallstones. In contrast, treatment with ezetimibe at 0.8 to 8 mg/kg/day induces rapid dissolution of gallstones. Gallstones were completely dissolved by the highest (8 mg/kg/day) dose of ezetimibe. (b) Representative photomicrographs of mucin gel, liquid crystals, cholesterol monohydrate crystals, and gallstones as observed in gallbladder biles at week 8 after ezetimibe treatment. All magnifications are ×800, except for ezetimibe treatment at 0 and 0.8 mg/kg/day, which are ×400, by polarizing light microscopy. (c) The relative lipid composition of pooled gallbladder bile from mice fed 8 weeks with the chow diet supplemented with varying doses of ezetimibe is plotted on a condensed phase diagram. Because of a 12-week feeding period of the lithogenic diet, the relative lipid composition of pooled gallbladder bile from mice that have formed cholesterol gallstones is located in the central three-phase zone. Although the lithogenic diet is replaced with the chow diet for 8 weeks, the relative biliary lipid composition of bile is still in region C, where at equilibrium the bile is composed of solid cholesterol crystals, liquid crystals, and saturated micelles. By feeding varying doses of ezetimibe, the relative lipid composition of pooled gallbladder bile gradually shifts down and, finally, enters the one-phase micellar zone. These alterations explain that gallstones are dissolved through an unsaturated micelle mechanism. A symbol * represents relative lipid composition of pooled gallbladder bile from mice that have preexisting gallstones and before ezetimibe treatment; ♦ relative lipid composition of pooled gallbladder bile at the end of the gallstone dissolution study at week 8 of feeding the chow diet only (control); ● 0.8; ▲ 4; ■ 8 mg/kg/day of ezetimibe. Reproduced with modifications and with permission from [15].