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1 Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235-8887; and 2 Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892
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 · kg1.
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.
neurodegeneration; cholesterol synthesis; lysosome; endoplasmic reticulum; low-density lipoprotein receptor
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