Ezetimibe prevents cholesterol gallstone formation in mice.
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.


OBJECTIVE
To test whether EZET can prevent gallstone formation in mice.


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.
Zúñiga
Silvia
S
Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
Molina
Héctor
H
Azocar
Lorena
L
Amigo
Ludwig
L
Nervi
Flavio
F
Pimentel
Fernando
F
Jarufe
Nicolás
N
Arrese
Marco
M
Lammert
Frank
F
Miquel
Juan F
JF
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001384:Azetidines / Q000494:pharmacology / Q000627:therapeutic use*; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D004195:Disease Models, Animal; D004386:Duodenum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000069438:Ezetimibe; D005260:Female; D042882:Gallstones / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL
D000924:Anticholesteremic Agents; D001384:Azetidines; D018955:CD36 Antigens; D002791:Cholesterol, Dietary; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C410800:NPC1L1 protein, human; C482445:Npc1l1 protein, mouse; D002784:Cholesterol; D000069438:Ezetimibe