Niemann-Pick type C1 (NPC1) disease is an autosomal-recessive 
cholesterol-storage disorder characterized by liver dysfunction, 
hepatosplenomegaly, and progressive neurodegeneration. The NPC1 gene is 
expressed in every tissue of the body, with liver expressing the highest amounts 
of NPC1 mRNA and protein. A number of studies have now indicated that the NPC1 
protein regulates the transport of cholesterol from late endosomes/lysosomes to 
other cellular compartments involved in maintaining intracellular cholesterol 
homeostasis. The present study characterizes liver disease and lipid metabolism 
in NPC1 mice at 35 days of age before the development of weight loss and 
neurological symptoms. At this age, homozygous affected (NPC1(-/-)) mice were 
characterized with mild hepatomegaly, an elevation of liver enzymes, and an 
accumulation of liver cholesterol approximately four times that measured in 
normal (NPC1(+/+)) mice. In contrast, heterozygous (NPC1(+/-)) mice were without 
hepatomegaly and an elevation of liver enzymes, but the livers had a significant 
accumulation of triacylglycerol. With respect to apolipoprotein and lipoprotein 
metabolism, the results indicated only minor alterations in NPC1(-/-) mouse 
serum. Finally, compared to NPC1(+/+) mouse livers, the amount and processing of 
SREBP-1 and -2 proteins were significantly increased in NPC1(-/-) mouse livers, 
suggesting a relative deficiency of cholesterol at the metabolically active pool 
of cholesterol located at the endoplasmic reticulum. The results from this study 
further support the hypothesis that an accumulation of lipoprotein-derived 
cholesterol within late endosomes/lysosomes, in addition to altered 
intracellular cholesterol homeostasis, has a key role in the biochemical and 
cellular pathophysiology associated with NPC1 liver disease.