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Cholesterol accumulation and liver cell death in mice with Niemann‐Pick type C disease
Author(s) -
Beltroy Eduardo P.,
Richardson James A.,
Horton Jay D.,
Turley Stephen D.,
Dietschy John M.
Publication year - 2005
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20868
Subject(s) - npc1 , niemann–pick disease , endocrinology , medicine , biology , cholesterol , liver disease , lysosomal storage disease , niemann–pick disease, type c , neurodegeneration , cell , disease , biochemistry , endosome
Abstract 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. (H EPATOLOGY 2005;42:886–893.)