title: Transgenic overexpression of Niemann-Pick C2 protein promotes cholesterol gallstone formation in mice.
abstract: OBJECTIVE
  Niemann-Pick C2 (NPC2) is a lysosomal protein involved in the egress of low-density lipoprotein-derived cholesterol from lysosomes to other intracellular compartments. NPC2 has been detected in several tissues and is also secreted from the liver into bile. We have previously shown that NPC2-deficient mice fed a lithogenic diet showed reduced biliary cholesterol secretion as well as cholesterol crystal and gallstone formation. This study aimed to investigate the consequences of NPC2 hepatic overexpression on liver cholesterol metabolism, biliary lipid secretion, gallstone formation and the effect of NPC2 on cholesterol crystallization in model bile.
  
  
  METHODS
  We generated NPC2 transgenic mice (Npc2.Tg) and fed them either chow or lithogenic diets. We studied liver cholesterol metabolism, biliary lipid secretion, bile acid composition and gallstone formation. We performed cholesterol crystallization studies in model bile using a recombinant NPC2 protein.
  
  
  RESULTS
  No differences were observed in biliary cholesterol content or secretion between wild-type and Npc2.Tg mice fed the chow or lithogenic diets. Interestingly, Npc2.Tg mice showed an increased susceptibility to the lithogenic diet, developing more cholesterol gallstones at early times, but did not show differences in the bile acid hydrophobicity and gallbladder cholesterol saturation indices compared to wild-type mice. Finally, recombinant NPC2 decreased nucleation time in model bile.
  
  
  CONCLUSIONS
  These results suggest that NPC2 promotes cholesterol gallstone formation by decreasing the cholesterol nucleation time, indicating a pro-nucleating function of NPC2 in bile.
authors.affiliation: Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile; FONDAP "Center for Genome Regulation" (CGR), Santiago, Chile.
authors.forename: Mariana
authors.initials: M
authors.lastname: Acuña
authors.affiliation: Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Lila
authors.initials: L
authors.lastname: González-Hódar
authors.affiliation: Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Amigo
authors.affiliation: Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Juan
authors.initials: J
authors.lastname: Castro
authors.affiliation: Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: M Gabriela
authors.initials: MG
authors.lastname: Morales
authors.affiliation: Neuroscience and Mental Health Program, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Gonzalo I
authors.initials: GI
authors.lastname: Cancino
authors.affiliation: Departments of Pediatrics/Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
authors.affiliation: Centro de Estudios Científicos (CECs), Valdivia, Chile.
authors.forename: Juan
authors.initials: J
authors.lastname: Young
authors.affiliation: Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile; FONDAP "Center for Genome Regulation" (CGR), Santiago, Chile.
authors.forename: Juan Francisco
authors.initials: JF
authors.lastname: Miquel
authors.affiliation: Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile; FONDAP "Center for Genome Regulation" (CGR), Santiago, Chile. Electronic address: silvana@med.puc.cl.
authors.forename: Silvana
authors.initials: S
authors.lastname: Zanlungo
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism; D003460:Crystallization; D004195:Disease Models, Animal; D042882:Gallstones / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008956:Models, Chemical; D013997:Time Factors; D033921:Vesicular Transport Proteins / Q000378:metabolism*
chemical_list: D001647:Bile Acids and Salts; C497045:Npc2 protein, mouse; D033921:Vesicular Transport Proteins; D002784:Cholesterol
keywords: Gallbladder; Lithiasis; Lithogenic diet; NPC2