Regulation of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Activity in Cultured Human Fibroblasts

作者：Michael Scott Brown, Suzanna E. Dana, Joseph L. Goldstein · 发表于：Journal of Biological Chemistry · 年份：1974 · DOI：10.1016/s0021-9258(19)42998-0 · 被引用次数：545 · 研究领域：Lipid metabolism and biosynthesis、Cholesterol and Lipid Metabolism、Peroxisome Proliferator-Activated Receptors

The activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-controlling enzyme in cholesterol biosynthesis, is suppressed in normal fibroblasts cultured in medium containing whole serum. The factor responsible for this suppression was localized to the low density and very low density lipoproteins, but was not found in high density lipoproteins. Whole serum from a patient with abetalipoproteinemia, which is deficient in apolipoprotein B (the protein common to low density and very low density lipoproteins), did not suppress the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Since cholesterol itself was able to suppress enzyme activity when added to cells in a non-lipoprotein form, the data indicate that low density and very low density lipoproteins reduce enzyme activity by delivering cholesterol to the cell. The cholesterol, in turn, acts to inhibit the synthesis of new 3-hydroxy-3-methylglutaryl coenzyme A reductase molecules. Cultured cells from a homozygote with the disorder familial hypercholesterolemia, which showed a nearly complete failure of suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity by low density or very low density lipoproteins, synthesized enzyme molecules at a rate nearly 60 times greater than that of normal cells. But when cholesterol was administered to these mutant cells in a non-lipoprotein form, it was able to exert a full inhibitory effect on 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, su...