title: Relevance of Niemann-Pick type C1 protein expression in controlling plasma cholesterol and biliary lipid secretion in mice.
abstract: Receptor-mediated endocytosis is one of the major mechanisms for uptake of lipoprotein cholesterol in the liver. Because Niemann-Pick C1 (NPC1) protein is a key component in the intracellular distribution of cholesterol obtained from lipoproteins by the endocytic pathway, it may play a critical role in controlling plasma lipoprotein cholesterol and its biliary secretion. A murine model of Niemann-Pick type C disease (NPC), the NPC1-deficient [NPC1 (-/-)] mouse, was used to evaluate the relevance of hepatic NPC1 expression in regulating plasma lipoprotein cholesterol profile and biliary lipid secretion under chow and high-cholesterol diets. Total plasma cholesterol concentrations were increased in NPC1 (-/-) mice compared with wild-type mice when both mouse strains were fed chow or high-cholesterol diets. The increased plasma cholesterol levels found in NPC1 (-/-) mice were mostly due to elevated cholesterol content in larger and more heterogeneous HDL particles. On the chow diet, biliary lipid secretion was not impaired by NPC1 deficiency. Furthermore, chow-fed NPC1 (-/-) mice showed a small, but significant, increase in biliary cholesterol secretion. On the high-cholesterol diet, wild-type mice increased biliary cholesterol output, whereas NPC1 (-/-) mice did not. Finally, hepatic NPC1 overexpression by adenovirus-mediated gene transfer increased biliary cholesterol secretion by 100% to 150% in both wild-type mice and cholesterol-fed NPC1 (-/-) mice. In conclusion, hepatic NPC1 expression is an important factor for regulating plasma HDL cholesterol levels and biliary cholesterol secretion in mice.
authors.affiliation: Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica, Santiago, Chile.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Amigo
authors.forename: Hegaly
authors.initials: H
authors.lastname: Mendoza
authors.forename: Juan
authors.initials: J
authors.lastname: Castro
authors.forename: Verónica
authors.initials: V
authors.lastname: Quiñones
authors.forename: Juan Francisco
authors.initials: JF
authors.lastname: Miquel
authors.forename: Silvana
authors.initials: S
authors.lastname: Zanlungo
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000256:Adenoviridae / Q000235:genetics; D000821:Animal Feed; D000818:Animals; D017734:Bile Ducts, Extrahepatic / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000097:blood*; D015870:Gene Expression; D018014:Gene Transfer Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008074:Lipoproteins / Q000235:genetics; D008099:Liver / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases / Q000378:metabolism*; D011506:Proteins / Q000235:genetics*
chemical_list: D018528:ATP-Binding Cassette Transporters; D002791:Cholesterol, Dietary; D047908:Intracellular Signaling Peptides and Proteins; D008074:Lipoproteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D002784:Cholesterol