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Deficiency of Niemann‐Pick C1 protein protects against diet‐induced gallstone formation in mice
Author(s) -
Morales María Gabriela,
Amigo Ludwig,
Balboa Elisa,
Acuña Mariana,
Castro Juan,
Molina Héctor,
Miquel Juan Francisco,
Nervi Flavio,
Rigotti Attilio,
Zanlungo Silvana
Publication year - 2010
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/j.1478-3231.2010.02230.x
Subject(s) - npc1 , medicine , cholesterol , endocrinology , cholic acid , gallstones , sterol , secretion , gallbladder , lipoprotein , biology , chemistry , receptor , endosome
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.