J. Lipid Res. Neurobiology of Lipids (ISSN1683-5506)
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Originally published In Press as doi:10.1194/jlr.M600488-JLR200 on January 14, 2007

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Journal of Lipid Research, Vol. 48, 869-881, April 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Lysosomal unesterified cholesterol content correlates with liver cell death in murine Niemann-Pick type C disease

Eduardo P. Beltroy, Benny Liu, John M. Dietschy and Stephen D. Turley1

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8887

Published, JLR Papers in Press, January 14, 2007.

1 To whom correspondence should be addressed. e-mail: stephen.turley{at}utsouthwestern.edu

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, 9–56 days) revealed a significant positive correlation between the plasma activities of alanine aminotransferase (ALT) and aspartate aminotransferase (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 increased by 72-fold by feeding a high-cholesterol, high-fat diet. These studies suggest that the late endosomal/lysosomal content of unesterified cholesterol correlates with cell damage in NPC disease.

Supplementary key words hepatic dysfunction • chylomicron cholesterol • low density lipoprotein receptor • biliary bile acid • hepatomegaly • small intestine

Abbreviations: ALT, alanine aminotransferase; apoE, apolipoprotein E; AST, aspartate aminotransferase; bw, body weight; CMr, chylomicron remnant; LDLR, low density lipoprotein receptor; NPC, Niemann-Pick type C; NPC1L1, Niemann-Pick C1-Like 1; VLDLr, very low density lipoprotein remnant


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