Alterations in the biosynthesis of cholesterol, dolichol and dolichyl-P in the genetic cholesterol homeostasis disorder, Niemann-Pick type C disease.
The biosynthesis of cholesterol, dolichol and dolichyl-P were investigated in a murine model of Niemann-Pick type C disease using both in vitro and in vivo systems. In vivo incorporation of [3H]mevalonate into squalene, dolichol and dolichyl-P decreased. The amount of dolichyl-P was elevated due to a decrease in the rate of degradation. Labeling of squalene and cholesterol of liver homogenates in vitro was decreased in the diseased mice and a lowering of microsomal activities of both HMG-CoA reductase and squalene synthase were also observed. In experiments with brain homogenate, decreased [3H]mevalonate labeling of squalene, cholesterol and dolichol was found in vitro. The decreases in cis-prenyltransferase and squalene synthase activities were observed at a very early phase of the disease. In contrast to the decreased biosynthesis of cholesterol observed in vitro, the labeling of total liver cholesterol was found to be increased in Niemann-Pick type C liver upon in vivo investigation, possibly due to the accumulation of this lipid as a result of a deficient transport process. In the brain, where in vivo labeling reflects only biosynthesis, a decreased rate of cholesterol synthesis was demonstrated.
Schedin
S
S
Department of Biochemistry, Stockholm University, S-10691 Stockholm, Sweden.
Nilsson
M
M
Chojnacki
T
T
Dallner
G
G
D000818:Animals; D001921:Brain / Q000378:metabolism; D002784:Cholesterol / Q000096:biosynthesis*; D004195:Disease Models, Animal; D004288:Dolichol Phosphates / Q000096:biosynthesis*; D004286:Dolichols / Q000096:biosynthesis*; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000378:metabolism; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000201:enzymology; D009542:Niemann-Pick Diseases / Q000378:metabolism*; D013185:Squalene / Q000378:metabolism; D014166:Transferases / Q000378:metabolism; D014316:Tritium
D004288:Dolichol Phosphates; D004286:Dolichols; D014316:Tritium; C028306:dolichol monophosphate; D013185:Squalene; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D014166:Transferases; C106821:cis-prenyl transferase; D013186:Farnesyl-Diphosphate Farnesyltransferase; D008798:Mevalonic Acid