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Papers In Press, published online ahead of print January 14, 2007
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Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-8887
Corresponding Author: stephen.turley{at}utsouthwestern.edu
Abstract Niemann-Pick type C (NPC) disease is a multisystem disorder resulting from mutations in the NPC1 gene that encodes a protein involved in intracellular cholesterol trafficking. Significant liver dysfunction is frequently seen in patients with this disease. The current studies used npc1-mutant mice to investigate the association between liver dysfunction and unesterified cholesterol accumulation, a hallmark of NPC disease. Data from 92 npc1-/- mice (age range 9 to 56 days) revealed a significant positive correlation between the plasma activities of ALT and AST and whole liver cholesterol content. In 56 day-old npc1-/- mice that had been fed from 35 days of age a rodent diet or the same diet containing either cholesterol (1.0% w/w) or ezetimibe (a sterol absorption inhibitor) (0.0125% w/w), whole liver cholesterol content averaged 33.5 ± 1.1, 87.9 ± 1.7 and 20.8 ± 0.9 mg, respectively. Again, plasma ALT and AST activities were positively correlated with hepatic cholesterol content. In contrast, plasma transaminase levels remained in the normal range in npc1+/+ mice in which hepatic esterified cholesterol content had been raised 72-fold by feeding a high cholesterol, high fat diet. These studies suggest it is the late endosomal/lysosomal content of unesterified cholesterol that correlates with cell damage in NPC disease.
Revised on January 11, 2007
Accepted on January 14, 2007
Lysosomal unesterified cholesterol content correlates with liver cell death in murine Niemann-Pick type C disease
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