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 investig ated in a murine model of Niemann-Pick type C disease using both in vi tro and in vivo systems. In vivo incorporation of [H-3]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 o f 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 experim ents with brain homogenate, decreased [H-3]mevalonate labeling of squa lene, cholesterol and dolichol was found in vitro. The decreases in ci s-prenyltransferase and squalene synthase activities were observed at a very early phase of the disease. In contrast to the decreased biosyn thesis of cholesterol observed in vitro, the labeling of total liver c holesterol 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 choleste rol synthesis was demonstrated. (C) 1998 Elsevier Science B.V. All rig hts reserved.