Niemann-Pick C2 protein expression regulates lithogenic diet-induced gallstone formation and dietary cholesterol metabolism in mice.
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.
Departmento de Gastroenterología, Escuela de Medicina, Facultad de Medicina, Pontificia Universidad Católica de Chile, Marcoleta 367, Casilla 114-D, Santiago, Chile.
Elisa
E
Balboa
Gabriela
G
Morales
Paula
P
Aylwin
Gonzalo
G
Carrasco
Ludwig
L
Amigo
Juan
J
Castro
Attilio
A
Rigotti
Silvana
S
Zanlungo
D000818:Animals; D001646:Bile / Q000378:metabolism*; D001692:Biological Transport / Q000235:genetics; D002791:Cholesterol, Dietary / Q000378:metabolism*; D004032:Diet / Q000009:adverse effects*; D042882:Gallstones / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D060888:Real-Time Polymerase Chain Reaction; D033921:Vesicular Transport Proteins / Q000172:deficiency / Q000235:genetics
D002791:Cholesterol, Dietary; C497045:Npc2 protein, mouse; D033921:Vesicular Transport Proteins