Centripetal cholesterol flow from the extrahepatic organs through the liver is normal in mice with mutated Niemann-Pick type C protein (NPC1)

Niemann-Pick type C (NPC) protein functions to move unesterified cholestero l from the lysosomal compartment to other intracellular sites for further m etabolism and/or excretion, This cholesterol is brought into the cell throu gh the coated-pit pathway and accumulates in the lysosomes when NPC protein is mutated, The present study quantitated the alternative uptake process t hat brings cholesterol into the cell through the scavenger receptor, class B, type I (SR-BI) pathway in animals with this mutation, In homozygous NPC mice, the tissues of the extrahepatic compartment accumulated an excess of 14 mg of cholesterol each day per kg body weight, and synthesis increased b y a similar amount (to 111 mg/day per kg) to compensate for this functional loss of sterol through lysosomal sequestration, An amount of cholesterol ( 108 mg/day per kg) nearly equal to that synthesized in the extrahepatic com partment was carried through the circulation by high density lipoprotein (H DL) and taken up by the liver, The rate of hepatic cholesterol excretion fr om the NPC mice as fecal acidic (65 mg/day per kg) and neutral (85 mg/day p er kg) sterols was elevated 61% above control values and was accounted for by the total amount of cholesterol brought to the liver in HDL and synthesi zed in the hepatocytes.jlr These studies demonstrated that while cholestero l entering tissues of the NPC animals through the coated-pit pathway became sequestered in the lysosomal compartment and was metabolically inactive, c holesterol that was newly synthesized or that entered cells through the SR- BI pathway was metabolized and excreted normally.