TY - JOUR
T1 - Cholesterol balance and metabolism in mice with loss of function of Niemann-Pick C protein
AU - Xie, Chonglun
AU - Turley, Stephen D.
AU - Pentchev, Peter G.
AU - Dietschy, John M.
PY - 1999/2
Y1 - 1999/2
N2 - Type C Niemann-Pick disease is due to a mutation in Niemann-Pick C (NPC) protein, a putative determinant of intracellular cholesterol transport. This study quantifies cholesterol balance in vivo across all tissues in mice with this defect. Cholesterol balance in the heterozygous animal is normal, but in the homozygous mouse the whole animal cholesterol pool expands continuously from birth, reaching 5,442 mg/kg at 7 wk. The size of this pool in each organ is proportional to the rate at which each tissue clears low-density lipoprotein-cholesterol. Despite this expansion, however, cholesterol synthesis is increased so that whole animal synthesis equals 180 mg · day- 1 · kg-1. Forcing additional cholesterol into the liver through the clathrin-coated pit pathway increases the hepatic cholesterol pool in control mice, all of which is esterified, while there is a much greater increase in this pool in mutant mice, all of which is unesterified. These findings are consistent with the view that there is a block in sterol movement from the lysosome to the sites of regulation in NPC disease and have important implications for understanding the function of the NPC protein in intracellular cholesterol metabolism, in general, and in the brain, in particular.
AB - Type C Niemann-Pick disease is due to a mutation in Niemann-Pick C (NPC) protein, a putative determinant of intracellular cholesterol transport. This study quantifies cholesterol balance in vivo across all tissues in mice with this defect. Cholesterol balance in the heterozygous animal is normal, but in the homozygous mouse the whole animal cholesterol pool expands continuously from birth, reaching 5,442 mg/kg at 7 wk. The size of this pool in each organ is proportional to the rate at which each tissue clears low-density lipoprotein-cholesterol. Despite this expansion, however, cholesterol synthesis is increased so that whole animal synthesis equals 180 mg · day- 1 · kg-1. Forcing additional cholesterol into the liver through the clathrin-coated pit pathway increases the hepatic cholesterol pool in control mice, all of which is esterified, while there is a much greater increase in this pool in mutant mice, all of which is unesterified. These findings are consistent with the view that there is a block in sterol movement from the lysosome to the sites of regulation in NPC disease and have important implications for understanding the function of the NPC protein in intracellular cholesterol metabolism, in general, and in the brain, in particular.
KW - Cholesterol synthesis
KW - Endoplasmic reticulum
KW - Low-density lipoprotein receptor
KW - Lysosome
KW - Neurodegeneration
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U2 - 10.1152/ajpendo.1999.276.2.e336
DO - 10.1152/ajpendo.1999.276.2.e336
M3 - Article
C2 - 9950794
AN - SCOPUS:0033049909
SN - 0193-1849
VL - 276
SP - E336-E344
JO - American Journal of Physiology - Endocrinology and Metabolism
JF - American Journal of Physiology - Endocrinology and Metabolism
IS - 2 39-2
ER -