Ezetimibe prevents cholesterol gallstone formation in mice

Zuñiga, S.; Molina, H; Azócar L.; Amigo, L; Nervi, F; Pimentel, F; Jarufe, N; Arrese M.; Lammert, F; Miquel, JF


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. © Journal compilation © 2008 Blackwell Munksgaard.

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Título según WOS: Ezetimibe prevents cholesterol gallstone formation in mice
Título según SCOPUS: Ezetimibe prevents cholesterol gallstone formation in mice
Título de la Revista: LIVER INTERNATIONAL
Volumen: 28
Número: 7
Editorial: Wiley
Fecha de publicación: 2008
Página de inicio: 935
Página final: 947
Idioma: English
URL: http://doi.wiley.com/10.1111/j.1478-3231.2008.01808.x