Search

Niemann-Pick C2 protein (NPC2) is a lysosomal soluble protein that is highly expressed in the liver; it binds to cholesterol and is involved in intracellular cholesterol trafficking, allowing the exit of lysosomal cholesterol obtained via the lipoprotein endocytic pathway. Thus, this protein may play an important role in controlling hepatic cholesterol transport and metabolism. The aim of this work was to study the relevance of NPC2 protein expression in hepatic cholesterol metabolism, biliary lipid secretion and gallstone formation by comparing NPC2 hypomorph [NPC2 (h/h)] and wild-type mice fed control, 2% cholesterol, and lithogenic diets. NPC2 (h/h) mice exhibited resistance to a diet-induced increase in plasma cholesterol levels. When consuming the chow diet, we observed increased biliary cholesterol and phospholipid secretions in NPC2 (h/h) mice. When fed the 2% cholesterol diet, NPC2 (h/h) mice exhibited low and high gallbladder bile cholesterol and phospholipid concentrations, respectively. NPC2 (h/h) mice fed with the lithogenic diet showed reduced biliary cholesterol secretion, gallbladder bile cholesterol saturation, and cholesterol crystal and gallstone formation. This work indicates that hepatic NPC2 expression is an important factor in the regulation of diet-derived cholesterol metabolism and disposal as well as in diet-induced cholesterol gallstone formation in mice.

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.