Niemann-Pick type C (NPC) disease develops as a result of mutations in the NPC1 gene that encodes a protein involved in the net movement of unesterified cholesterol from the late endosomal/lysosomal compartment to the metabolically active pool of sterol in the cytosol of virtually every cell in the body. Although early publications emphasized the neurodegeneration occurring in children with this mutation, more recent clinical information suggests that serious liver disease also is an important part of this syndrome. These studies, therefore, were undertaken to characterize the liver dysfunction seen in mice with this same mutation. The NPC mouse develops significant hepatomegaly that reaches 8% of body weight at 5 to 6 weeks of age. This increase in liver size is associated with a linear increase in cholesterol content and with accumulation of amorphous cellular inclusions in both hepatocytes and macrophages. During the few weeks after birth, significant elevation of the plasma alkaline phosphatase level occurs, as also is seen in the human infant with this disease. At 4 to 5 weeks of age, plasma aminotransferase levels also rise abruptly. Histologically, at this time there is apoptosis, but no excess deposition of collagen or glycogen. mRNA expression is elevated for caspase 1, caspase 6, and several enzymes associated with sterol biosynthesis and bile acid formation. In conclusion, the NPC mouse has liver disease similar to that seen in the NPC infant and represents a relevant model for exploring the molecular events occurring in this form of liver disease. (HEPATOLOGY 2005;42:886-893.) N iemann-Pick type C (NPC) disease is an autosomal recessive lipid storage disorder characterized by enlargement of the liver and spleen, progressive hepatic and neurological deterioration, and death in the second or third decade of life. 1 The mutation responsible for approximately 95% of these cases has been mapped to a gene on chromosome 18q11 designated NPC1. 2 This gene encodes a protein (NPC1) with 5 transmembrane domains that share homology with the sterol-sensing domain of 2 enzymes involved in cellular cholesterol homeostasis, 3-hydroxy-3-methylglutaryl co-enzyme A reductase and sterol regulatory element binding protein cleavage-activating protein. 2,3 Most cells in the body take up cholesterol from the surrounding environment, using one or more members of the low-density lipoprotein receptor (LDLR) family, and then process this sterol through the clathrin-coated pit pathway to the metabolically accessible pool of sterol in the cytosol. [4][5][6] Because the NPC1 protein apparently functions to move unesterified cholesterol from the late endosomal/lysosomal compartment of these cells to the metabolically active pool, the characteristic finding in the child (or mouse) with a mutation of this protein is the progressive accumulation of sterol in every tissue. [7][8][9][10] However, the magnitude of this accumulation varies in different organs, depending on how much cholesterol is normally taken up through the clathrin-coated pit pathway in each of these particular tissues. 11 Liver plays the key role in the clearance of circulating cholesterol carried in lipoproteins and so manifests the highest rate of sterol accumulation in both the human and mouse with a mutation in NPC1. 5,7,9 The pathways responsible for this accumulation are outlined diagrammatically in Fig. 1. Cholesterol absorbed from the intestine and carried in the chylomicron remnant (CMr) is nearly completely cleared into the liver, using the LDLR and