Deficiency of Niemann-Pick C1 protein protects against diet-induced gallstone formation in mice

Authors


Correspondence
Silvana Zanlungo, PhD, Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Marcoleta 367, Casilla 114-D, Santiago,
Chile
Tel: +56-2-686 3833
Fax: +56-2-639 7780
e-mail: silvana@med.puc.cl

Abstract

Background/aims: Receptor-mediated endocytosis is a critical cellular mechanism for the uptake of lipoprotein cholesterol in the liver. Because Niemann-Pick C1 (NPC1) protein is a key component for the intracellular distribution of cholesterol originating from lipoprotein endocytosis, it may play an important role in controlling biliary cholesterol secretion and gallstone formation induced by a lithogenic diet.

Methods: We studied biliary cholesterol secretion, gallbladder lipid composition and gallstone formation in NPC1-deficient mice fed a low-fat lithogenic diet (1.5% cholesterol and 0.5% cholic acid) compared with control animals under the same diet.

Results: The lipid secretion response to the lithogenic diet was impaired in NPC1 (−/−) mice, leading to a decreased cholesterol output and an increased hepatic cholesterol concentration compared with the lithogenic diet-fed wild-type mice. A decreased cholesterol saturation index was found in the gallbladder bile of NPC1 (+/−) and (−/−) mice after lithogenic diet feeding. Consequently, mice with a partial or a total deficiency of NPC1 had a drastically lower frequency of gallbladder cholesterol crystals and a reduced prevalence of gallstones.

Conclusion: Hepatic NPC1 expression is an important factor for regulating the biliary secretion of diet-derived cholesterol as well as for diet-induced cholesterol gallstone formation in mice.

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