Abstract
HMG-CoA reductase activity, 14C-acetate incorporation into cholesterol and cholesteryl ester formation were studied in fibroblasts from 6 patients with mevalonic aciduria due to mevalonate kinase deficiency (MK−) in response to different concentrations of LDL and non-lipoprotein cholesterol. Despite a virtually complete deficiency of mevalonate kinase in extracts of fibroblasts derived from the patients, there was still significant activity for the cholesterol biosynihetic pathway, assessed by monitoring 14C-acetate incorporation into cholesterol in intact fibroblast monolayers. In the presence of LDL MK− cells produced -30% of the control cell lines and showed a significant increase into the control range after complete withdrawal of cholesterol. Adequate cholesterol biosynthesis was assured by a highly increased and partially unsuppressable HMG-CoA reductase activity in MK− cells as compared to controls. For patients, the mean activity of HMG-CoA reductase of 63.3 ± 44.1 pmol/min/mg protein (± ISD, range 37.7-146.2) was significantly higher than the mean value in control fibroblasts of 11.1 ± 3.5 (range 8.0-14.9). In addition, cholestyl ester formation, an indicator of the LDL receptor pathway, was twofold increased in the patients' cells, whereas cholestyl ester formation from non-lipoprotein cholesterol was undistinguishable from controls. Apparently an inhibition of intracellular cholesterol biosynthesis is counteracted by an increased activity of HMG-CoA reductase as well as of the LDL receptor pathway. The increased activity of the LDL receptor in the presence of an excess of exogenous cholesterol proves the existence of a single common regulatory mechanism of cholesterol biosynthesis and the LDL receptor pathway. The latter mechanism, which is demonstrated by this “experiment of nature”, should be reponsible for the observed reduction of LDL cholesterol in hypercholesterolemic patients by HMG-CoA reductase inhibitors. However, the long term use of these drugs cannot be recommended in children or pregnant women in view of the severe multisystemic pre- and postnatal pathology of mevalonic aciduria. The exact pathobiochemical mechanisms are still unclear and may involve a shortage of non-sterol isoprenes. (Supported by DFG grant Ho 966/2-2)
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Hoffmann, G., Gibson, K. 30 REGULATORY ADAPTATION OF CHOLESTEROL BIOSYNTHESIS AND THE LDL-RECEPTOR PATHWAY IN MEVALONIC ACIDURIA. Pediatr Res 28, 282 (1990). https://doi.org/10.1203/00006450-199009000-00054
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DOI: https://doi.org/10.1203/00006450-199009000-00054