title: Liver disease with altered bile acid transport in Niemann-Pick C mice on a high-fat, 1% cholesterol diet.
abstract: Cholestatic hepatitis is frequently found in Niemann-Pick C (NPC) disease. We studied the influence of diet and the low density lipoprotein receptor (LDLR, Ldlr in mice, known to be the source of most of the stored cholesterol) on liver disease in the mouse model of NPC. Npc1-/- mice of both sexes, with or without the Ldlr knockout, were fed a 18% fat, 1% cholesterol ("high-fat") diet and were evaluated by chemical and histological methods. Bile acid transporters [multidrug resistance protein (Mrps) 1-5; Ntcp, Bsep, and OatP1, 2, and 4] were quantitated by real-time RT-PCR. Many mice died prematurely (within 6 wk) with hepatomegaly. Histopathology showed an increase in macrophage and hepatocyte lipids independent of Ldlr genotype. Non-zone-dependent diffuse fibrosis was found in the surviving mice. Serum alanine aminotransferase was elevated in Npc1-/- mice on the regular diet and frequently became markedly elevated with the high-fat diet. Serum cholesterol was increased in the controls but not the Npc1-/- mice on the high-fat diet; it was massively increased in the Ldlr-/- mice. Esterified cholesterol was greatly increased by the high-fat diet, independent of Ldlr genotype. gamma-Glutamyltransferase was also elevated in Npc1-/- mice, more so on the high-fat diet. Mrps 1-5 were elevated in Npc1-/- liver and became more elevated with the high-fat diet; Ntcp, Bsep, and OatP2 were elevated in Npc1-/- liver and were suppressed by the high-fat diet. In conclusion, Npc1-/- mice on a high-fat diet provide an animal model of NPC cholestatic hepatitis and indicate a role for altered bile acid transport in its pathogenesis.
authors.affiliation: Department of Pediatrics, School of Health Sciences, University of Arizona, 1501 N. Campbell Avenue, P. O. Box 245073, Tucson, AZ 85724-5073. erickson@peds.arizona.edu
authors.forename: Robert P
authors.initials: RP
authors.lastname: Erickson
authors.forename: Achyut
authors.initials: A
authors.lastname: Bhattacharyya
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Hunter
authors.forename: Randall A
authors.initials: RA
authors.lastname: Heidenreich
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Cherrington
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002791:Cholesterol, Dietary / Q000493:pharmacokinetics*; D005260:Female; D006505:Hepatitis / Q000209:etiology / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases / Q000150:complications / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics; D027701:Organic Cation Transport Proteins / Q000235:genetics; D011506:Proteins / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics
chemical_list: D001647:Bile Acids and Salts; D002791:Cholesterol, Dietary; D047908:Intracellular Signaling Peptides and Proteins; D027381:Liver-Specific Organic Anion Transporter 1; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; C464433:Oatp2 protein, mouse; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; D011506:Proteins; D011973:Receptors, LDL; C498887:Slco1b2 protein, mouse