REGULATORY ADAPTATION OF ISOPRENOID BIOSYNTHESIS AND THE LDL RECEPTORPATHWAY IN FIBROBLASTS FROM PATIENTS WITH MEVALONATE KINASE-DEFICIENCY

In a search for the pathophysiologic mechanisms, we estimated isopreno id synthesis and concentration, cellular growth, and the activity of t he LDL receptor pathway in fibroblasts from patients with mevalonate k inase deficiency (MKD), a severe multisystemic disorder of cholesterol and non-sterol isoprenoid biosynthesis. In response to different conc entrations of LDL and non-lipoprotein-bound cholesterol, MKD cells par tially counteracted their enzyme defect by increased activities of 3-h ydroxy-3-methylglutaryl (HMG)-CoA reductase (results from earlier stud ies) and the LDL receptor pathway, responses similar to the pharmacolo gic effects seen upon administration of HMG-CoA reductase inhibitors. Rates of N-linked protein glycosylation, estimated as the amount of [C -14]galactose-labeled macromolecules secreted into cell culture medium , were significantly decreased in MKD fibroblasts in comparison with c ontrol cells, which may indicate alterations in the dolichol or dolich ol phosphate pool. In response to exogenous cholesterol, the major fee dback inhibitor of isoprenoid biosynthesis, growth velocities of MKD f ibroblasts declined in comparison with control cells, further suggesti ng an impairment of non-sterol isoprenoid biosynthesis in MKD. Our res ults suggest an imbalance in the multilevel regulation of the biosynth esis of cholesterol and nonsterol isoprenoids in MKD, representing an additional causative factor responsible for the pre- and postnatal pat hology of MKD.