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

Liver disease with altered bile acid transport in Niemann-Pick C mice on a high-fat, 1% cholesterol diet. Am J Physiol Gastrointest Liver Physiol 289: G300-G307, 2005. First published March 24, 2005; doi:10.1152/ajpgi.00568.2004.-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-zonedependent 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.