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Deficiency of Niemann-Pick C1 protein protects against diet-induced gallstone formation in mice
María Gabriela Morales1, Ludwig Amigo, Elisa Balboa
1Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
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.
