Ezetimibe prevents cholesterol gallstone formation in mice
Version of Record online: 8 JUL 2008
© 2008 The Authors. Journal compilation © 2008 Blackwell Munksgaard
Volume 28, Issue 7, pages 935–947, August 2008
How to Cite
Zúñiga, S., Molina, H., Azocar, L., Amigo, L., Nervi, F., Pimentel, F., Jarufe, N., Arrese, M., Lammert, F. and Miquel, J. F. (2008), Ezetimibe prevents cholesterol gallstone formation in mice. Liver International, 28: 935–947. doi: 10.1111/j.1478-3231.2008.01808.x
- Issue online: 8 JUL 2008
- Version of Record online: 8 JUL 2008
- Received 25 January 2008Accepted 11 May 2008
- biliary lipids;
- cholesterol gallstones;
- gall bladder
Background: Intestinal cholesterol absorption may influence gallstone formation and its modulation could be a useful therapeutic strategy for gallstone disease (GSD). Ezetimibe (EZET) is a cholesterol-lowering agent that specifically inhibits intestinal cholesterol absorption.
Aims: To test whether EZET can prevent gallstone formation in mice.
Methods/Results: Gallstone-susceptible C57BL/6 inbred mice were fed control and lithogenic diets with or without simultaneous EZET administration. Lithogenic diet increased biliary cholesterol content and secretion, and induced sludge or gallstone formation in 100% of the animals. EZET administration reduced intestinal cholesterol absorption by 90% in control animals and by 35% in mice receiving the lithogenic diet. EZET prevented the appearance of cholesterol crystals and gallstones. In addition, mice fed the lithogenic diet plus EZET exhibited a 60% reduction in biliary cholesterol saturation index. Of note, EZET treatment caused a significant increase in bile flow (+50%, P<0.01) as well as bile salt, phospholipid and glutathione secretion rates (+60%, +44% and +100%, respectively, P<0.01), which was associated with a moderately increased expression of hepatic bile salt transporters. In addition, relative expression levels of Nieman–Pick C1 like 1 (NPC1L1) in the enterohepatic axis in humans were assessed. Expression levels of NPC1L1 were 15- to 30-fold higher in the duodenum compared with the liver at transcript and protein levels, respectively, suggesting preferential action of EZET on intestinal cholesterol absorption in humans.
Conclusions: In a murine model of GSD, EZET prevented gallstone formation by reducing intestinal cholesterol absorption and increasing bile salt-dependent and -independent bile flow. EZET could be useful in preventing GSD disease in susceptible patients.