HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 289/2/G300    most recent 00568.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (8) Citing Articles via Google Scholar Google Scholar Articles by Erickson, R. P. Articles by Cherrington, N. J. Search for Related Content PubMed PubMed Citation Articles by Erickson, R. P. Articles by Cherrington, N. J.

LIVER AND BILIARY TRACT

Liver disease with altered bile acid transport in Niemann-Pick C mice on a high-fat, 1% cholesterol diet

Departments of ¹Pediatrics, ²Pathology, and ³Pharmacology/Toxicology, University of Arizona, School of Health Sciences, Tucson, Arizona

Submitted 23 December 2004 ; accepted in final form 23 March 2005

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. -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.

Niemann-Pick C; low density lipoprotein receptor knockout; neonatal cholestasis; bile acid transporters; non-zone-dependent fibrosis