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

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.

mdr1a deficiency corrects sterility in Niemann-Pick C1 protein deficient female mice.

Niemann-Pick type C disease is a progressive neurological disease with cholesterol storage in liver, and npc1-/- mice share these features and are sterile. We have searched for the cause of sterility and found normal folliculogenesis and progesterone levels but lack of implantation. Multiple drug resistance (MDR) P-glycoproteins are plasma membrane proteins implicated in the movement of drugs and lipids across membranes. Their functions are inhibited by progesterone, which has been shown to alter cellular cholesterol homeostasis and has implicated P-glycoproteins in the movement of cholesterol to the endoplasmic reticulum. We have introduced the mdr1a knockout into the npc1 mutant line. While the neurological disease continues at its usual rate, preventing the females from taking care of their litters, npc1-/-, mdr1a-/- females became fertile. Although the mdr1a P-glycoprotein co-localizes with caveolae, neither caveolin-1 nor npc1 levels were significantly altered in the livers of double homozygotes. The absence of mdr1a was confirmed by immunoblotting, but npc1 deficiency was not associated with consistent changes in cerebellar mdr1a in mdr1a+/+ mice. The results show that a mdr1a mutation is an in vivo suppressor of female sterility in npc1 deficient mice.