title: Characterization of liver disease and lipid metabolism in the Niemann-Pick C1 mouse.
abstract: Niemann-Pick type C1 (NPC1) disease is an autosomal-recessive cholesterol-storage disorder characterized by liver dysfunction, hepatosplenomegaly, and progressive neurodegeneration. The NPC1 gene is expressed in every tissue of the body, with liver expressing the highest amounts of NPC1 mRNA and protein. A number of studies have now indicated that the NPC1 protein regulates the transport of cholesterol from late endosomes/lysosomes to other cellular compartments involved in maintaining intracellular cholesterol homeostasis. The present study characterizes liver disease and lipid metabolism in NPC1 mice at 35 days of age before the development of weight loss and neurological symptoms. At this age, homozygous affected (NPC1(-/-)) mice were characterized with mild hepatomegaly, an elevation of liver enzymes, and an accumulation of liver cholesterol approximately four times that measured in normal (NPC1(+/+)) mice. In contrast, heterozygous (NPC1(+/-)) mice were without hepatomegaly and an elevation of liver enzymes, but the livers had a significant accumulation of triacylglycerol. With respect to apolipoprotein and lipoprotein metabolism, the results indicated only minor alterations in NPC1(-/-) mouse serum. Finally, compared to NPC1(+/+) mouse livers, the amount and processing of SREBP-1 and -2 proteins were significantly increased in NPC1(-/-) mouse livers, suggesting a relative deficiency of cholesterol at the metabolically active pool of cholesterol located at the endoplasmic reticulum. The results from this study further support the hypothesis that an accumulation of lipoprotein-derived cholesterol within late endosomes/lysosomes, in addition to altered intracellular cholesterol homeostasis, has a key role in the biochemical and cellular pathophysiology associated with NPC1 liver disease.
authors.affiliation: Department of Pediatrics, The University of Arizona, Tucson, AZ 85724, USA. wgarver@peds.arizona.edu
authors.forename: William S
authors.initials: WS
authors.lastname: Garver
authors.forename: David
authors.initials: D
authors.lastname: Jelinek
authors.forename: Janice N
authors.initials: JN
authors.lastname: Oyarzo
authors.forename: James
authors.initials: J
authors.lastname: Flynn
authors.forename: Matthew
authors.initials: M
authors.lastname: Zuckerman
authors.forename: Kumar
authors.initials: K
authors.lastname: Krishnan
authors.forename: Byung H
authors.initials: BH
authors.lastname: Chung
authors.forename: Randall A
authors.initials: RA
authors.lastname: Heidenreich
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000033:anatomy & histology / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases; D009929:Organ Size; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D047908:Intracellular Signaling Peptides and Proteins; D008074:Lipoproteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D051779:Sterol Regulatory Element Binding Proteins; D002784:Cholesterol