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

Publisher: Wiley-Blackwell Country of Publication: United States NLM ID: 101160857 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1478-3231 (Electronic) Linking ISSN: 14783223 NLM ISO Abbreviation: Liver Int Subsets: MEDLINE

Publication: Malden, MA : Wiley-Blackwell
Original Publication: Oxford, UK : Blackwell Munksgaard, c2003-

Bile/*metabolism ; Cholesterol, Dietary/*metabolism ; Gallstones/*prevention & control ; Liver/*metabolism ; Proteins/*metabolism; ATP-Binding Cassette Transporters/genetics ; Animals ; Biological Transport ; Cholesterol 7-alpha-Hydroxylase/genetics ; Cholic Acid ; Disease Models, Animal ; Gallstones/chemically induced ; Gallstones/genetics ; Gallstones/metabolism ; Gene Expression Regulation ; Hydroxymethylglutaryl CoA Reductases/genetics ; Intracellular Signaling Peptides and Proteins ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Knockout ; Niemann-Pick C1 Protein ; Proteins/genetics ; RNA, Messenger/metabolism ; Receptors, LDL/genetics ; Sterol Regulatory Element Binding Protein 2/genetics ; Vesicular Transport Proteins/genetics

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.

0 (ATP-Binding Cassette Transporters)
0 (Cholesterol, Dietary)
0 (Intracellular Signaling Peptides and Proteins)
0 (Niemann-Pick C1 Protein)
0 (Npc1 protein, mouse)
0 (Npc2 protein, mouse)
0 (Proteins)
0 (RNA, Messenger)
0 (Receptors, LDL)
0 (Srebf2 protein, mouse)
0 (Sterol Regulatory Element Binding Protein 2)
0 (Vesicular Transport Proteins)
EC 1.1.1.- (Hydroxymethylglutaryl CoA Reductases)
EC 1.14.14.23 (Cholesterol 7-alpha-Hydroxylase)
EC 1.14.14.23 (Cyp7a1 protein, mouse)
G1JO7801AE (Cholic Acid)

Date Created: 20100423 Date Completed: 20101026 Latest Revision: 20211203

20221213

10.1111/j.1478-3231.2010.02230.x

20408952