TY - JOUR
T1 - Receptor-mediated and bulk-phase endocytosis cause macrophage and cholesterol accumulation in Niemann-Pick C disease
AU - Liu, Benny
AU - Xie, Chonglun
AU - Richardson, James A.
AU - Turley, Stephen D.
AU - Dietschy, John M.
PY - 2007/8
Y1 - 2007/8
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Hepatic dysfunction
KW - Lipoprotein clearance
KW - Low density lipoprotein receptor
KW - Lung failure
KW - Lysosomal cholesterol
KW - Neurodegeneration
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U2 - 10.1194/jlr.M700125-JLR200
DO - 10.1194/jlr.M700125-JLR200
M3 - Article
C2 - 17476031
AN - SCOPUS:34548162714
SN - 0022-2275
VL - 48
SP - 1710
EP - 1723
JO - Journal of lipid research
JF - Journal of lipid research
IS - 8
ER -