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

Niemann-Pick type C (NPC) disease is associated with the accumulation of un esterified cholesterol in nearly all tissues and with progressive neurodege neration. A murine model of this disease, the NPC mouse, was used to determ ine 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 N PC 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. T his was 7-fold greater than the rate of accumulation in control mice. The r ate of LDL clearance in the NPC mouse was normal (523 ml/day per kg) and ac counted 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 mi ce altered the concentration of unesterified cholesterol in every organ in a manner consistent with the changes also observed in the rate of LDL chole sterol uptake in those tissues. Similarly, altering the flow of cholesterol to the liver through the CM pathway changed the concentration of unesterif ied cholesterol in that organ. Together, these observations strongly suppor t 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 synthe sized and carried in high density lipoprotein.