J. Lipid Res. Neurobiology of Lipids (ISSN1683-5506)
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Originally published In Press as doi:10.1194/jlr.M700125-JLR200 on May 2, 2007

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Journal of Lipid Research, Vol. 48, 1710-1723, August 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Receptor-mediated and bulk-phase endocytosis cause macrophage and cholesterol accumulation in Niemann-Pick C disease

Benny Liu*, Chonglun Xie*, James A. Richardson{dagger}, Stephen D. Turley* and John M. Dietschy1,*

* Department of Internal Medicine, University of Texas Southwestern Medical School, Dallas, TX 75390-9151
{dagger} Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX 75390-9151

Published, JLR Papers in Press, May 2, 2007.

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

These studies explored the roles of receptor-mediated and bulk-phase endocytosis as well as macrophage infiltration in the accumulation of cholesterol in the mouse with Niemann-Pick type C (NPC) disease. Uptake of LDL-cholesterol varied from 514 µg/day in the liver to zero in the central nervous system. In animals lacking LDL receptors, liver uptake remained about the same (411 µg/day), but more cholesterol was taken up in extrahepatic organs. This uptake was unaffected by the reductive methylation of LDL and consistent with bulk-phase endocytosis. All tissues accumulated cholesterol in mice lacking NPC1 function, but this accumulation was decreased in adrenal, unchanged in liver, and increased in organs like spleen and lung when LDL receptor function was also deleted. Over 56 days, the spleen and lung accumulated amounts of cholesterol greater than predicted, and these organs were heavily infiltrated with macrophages. This accumulation of both cholesterol and macrophages was increased by deleting LDL receptor function. These observations indicate that both receptor-mediated and bulk-phase endocytosis of lipoproteins, as well as macrophage infiltration, contribute to the cholesterol accumulation seen in NPC disease. These macrophages may also play a role in parenchymal cell death in this syndrome.

Supplementary key words hepatic dysfunction • lung failure • low density lipoprotein receptor • lysosomal cholesterol • apoptosis • neurodegeneration • lipoprotein clearance

Abbreviations: apoE, apolipoprotein E; CMr, chylomicron remnant; LDL-TC, total cholesterol carried in LDL; LDLR, low density lipoprotein receptor; NPC, Niemann-Pick type C; VLDLr, very low density lipoprotein remnant


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