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.