title: Cholesterol accumulation and liver cell death in mice with Niemann-Pick type C disease.
abstract: Niemann-Pick type C (NPC) disease develops as a result of mutations in the NPC1 gene that encodes a protein involved in the net movement of unesterified cholesterol from the late endosomal/lysosomal compartment to the metabolically active pool of sterol in the cytosol of virtually every cell in the body. Although early publications emphasized the neurodegeneration occurring in children with this mutation, more recent clinical information suggests that serious liver disease also is an important part of this syndrome. These studies, therefore, were undertaken to characterize the liver dysfunction seen in mice with this same mutation. The NPC mouse develops significant hepatomegaly that reaches 8% of body weight at 5 to 6 weeks of age. This increase in liver size is associated with a linear increase in cholesterol content and with accumulation of amorphous cellular inclusions in both hepatocytes and macrophages. During the few weeks after birth, significant elevation of the plasma alkaline phosphatase level occurs, as also is seen in the human infant with this disease. At 4 to 5 weeks of age, plasma aminotransferase levels also rise abruptly. Histologically, at this time there is apoptosis, but no excess deposition of collagen or glycogen. mRNA expression is elevated for caspase 1, caspase 6, and several enzymes associated with sterol biosynthesis and bile acid formation. In conclusion, the NPC mouse has liver disease similar to that seen in the NPC infant and represents a relevant model for exploring the molecular events occurring in this form of liver disease.
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical School, Dallas, TX 75390-8887, USA.
authors.forename: Eduardo P
authors.initials: EP
authors.lastname: Beltroy
authors.forename: James A
authors.initials: JA
authors.lastname: Richardson
authors.forename: Jay D
authors.initials: JD
authors.lastname: Horton
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Turley
authors.forename: John M
authors.initials: JM
authors.lastname: Dietschy
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001921:Brain / Q000378:metabolism; D020170:Caspase 1 / Q000235:genetics; D053178:Caspase 6; D020169:Caspases / Q000235:genetics; D002784:Cholesterol / Q000378:metabolism*; D004041:Dietary Fats / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009929:Organ Size; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D004041:Dietary Fats; D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D002784:Cholesterol; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C505514:CASP6 protein, human; C505516:Casp6 protein, mouse; D053178:Caspase 6; D020169:Caspases; D020170:Caspase 1