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


CONCLUSIONS
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.
Morales
María Gabriela
MG
Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
Amigo
Ludwig
L
Balboa
Elisa
E
Acuña
Mariana
M
Castro
Juan
J
Molina
Héctor
H
Miquel
Juan Francisco
JF
Nervi
Flavio
F
Rigotti
Attilio
A
Zanlungo
Silvana
S
D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D001646:Bile / Q000378:metabolism*; D001692:Biological Transport; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics; D002791:Cholesterol, Dietary / Q000378:metabolism*; D019826:Cholic Acid; D004195:Disease Models, Animal; D042882:Gallstones / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D005786:Gene Expression Regulation; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D000077296:Niemann-Pick C1 Protein; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics; D033921:Vesicular Transport Proteins / Q000235:genetics
D018528:ATP-Binding Cassette Transporters; D002791:Cholesterol, Dietary; D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; C497045:Npc2 protein, mouse; D011506:Proteins; D012333:RNA, Messenger; D011973:Receptors, LDL; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D033921:Vesicular Transport Proteins; D006903:Hydroxymethylglutaryl CoA Reductases; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse; D019826:Cholic Acid