TY - JOUR
T1 - Cholesterol accumulation in tissues of the Niemann-Pick type C mouse is determined by the rate of lipoprotein-cholesterol uptake through the coated-pit pathway in each organ
AU - Xie, C.
AU - Turley, S. D.
AU - Dietschy, J. M.
PY - 1999/10/12
Y1 - 1999/10/12
N2 - Niemann-Pick type C (NPC) disease is associated with the accumulation of unesterified cholesterol in nearly all tissues and with progressive neurodegeneration. A murine model of this disease, the NPC mouse, was used to determine whether this sequestered cholesterol represented sterol carried in low density lipoprotein (LDL) and chylomicrons (CMs) taken up into the tissues through the coated-pit pathway. By 7 weeks of age, the sterol pool in the NPC mice had increased from 2,165 to 5,669 mg/kg body weight because of the daily sequestration of 67 mg of cholesterol per kg in the various organs. This was 7-fold greater than the rate of accumulation in control mice. The rate of LDL clearance in the NPC mouse was normal (523 ml/day per kg) and accounted for the uptake of 78 mg/day per kg of cholesterol in LDL whereas 8 mg/day per kg was taken up from CMs. Deletion of the LDL receptor in NPC mice altered the concentration of unesterified cholesterol in every organ in a manner consistent with the changes also observed in the rate of LDL cholesterol uptake in those tissues. Similarly, altering the flow of cholesterol to the liver through the CM pathway changed the concentration of unesterified cholesterol in that organ. Together, these observations strongly support the conclusion that, in NPC disease, it is cholesterol carried in LDL and CMs that is sequestered in the tissues and not sterol that is newly synthesized and carried in high density lipoprotein.
AB - Niemann-Pick type C (NPC) disease is associated with the accumulation of unesterified cholesterol in nearly all tissues and with progressive neurodegeneration. A murine model of this disease, the NPC mouse, was used to determine whether this sequestered cholesterol represented sterol carried in low density lipoprotein (LDL) and chylomicrons (CMs) taken up into the tissues through the coated-pit pathway. By 7 weeks of age, the sterol pool in the NPC mice had increased from 2,165 to 5,669 mg/kg body weight because of the daily sequestration of 67 mg of cholesterol per kg in the various organs. This was 7-fold greater than the rate of accumulation in control mice. The rate of LDL clearance in the NPC mouse was normal (523 ml/day per kg) and accounted for the uptake of 78 mg/day per kg of cholesterol in LDL whereas 8 mg/day per kg was taken up from CMs. Deletion of the LDL receptor in NPC mice altered the concentration of unesterified cholesterol in every organ in a manner consistent with the changes also observed in the rate of LDL cholesterol uptake in those tissues. Similarly, altering the flow of cholesterol to the liver through the CM pathway changed the concentration of unesterified cholesterol in that organ. Together, these observations strongly support the conclusion that, in NPC disease, it is cholesterol carried in LDL and CMs that is sequestered in the tissues and not sterol that is newly synthesized and carried in high density lipoprotein.
UR - http://www.scopus.com/inward/record.url?scp=0032740439&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032740439&partnerID=8YFLogxK
U2 - 10.1073/pnas.96.21.11992
DO - 10.1073/pnas.96.21.11992
M3 - Article
C2 - 10518564
AN - SCOPUS:0032740439
SN - 0027-8424
VL - 96
SP - 11992
EP - 11997
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 21
ER -