Binding and Degradation of Low Density Lipoproteins by Cultured Human Fibroblasts

作者：Joseph L. Goldstein, Michael S. Brown · 发表于：Journal of Biological Chemistry · 年份：1974 · DOI：10.1016/s0021-9258(19)42341-7 · 被引用次数：1500 · 研究领域：Cancer, Lipids, and Metabolism、Diabetes, Cardiovascular Risks, and Lipoproteins、Ubiquitin and proteasome pathways

125I-Labeled low density lipoproteins were found to associate with monolayers of cultured normal fibroblasts by two processes—one of high affinity and one of low affinity. The high affinity association appeared to represent binding of the low density lipoprotein to specific receptor sites on the cell surface. This binding process exhibited saturation kinetics at low concentrations of the lipoprotein and competition by related molecules such as very low density lipoproteins. In addition, this process was stimulated by the presence of calcium in the culture medium and could be destroyed by limited treatment of the cells with pronase. The other process, designated low affinity uptake, may represent nonspecific endocytosis since the uptake was proportional to the lipoprotein concentration in the medium with no apparent saturation and because it showed no competition by very low density lipoproteins, no stimulation by calcium, and no destruction by pronase treatment. The 125I-labeled low density lipoproteins associated with normal cells by either the high or low affinity process were degraded by proteolysis to trichloroacetic acid-soluble material, most of which was 125I-tyrosine. In normal cells, binding of low density lipoproteins to the high affinity membrane receptor sites appears to serve two functions: (a) it results in suppression of the synthesis of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-controlling enzyme in cholesterol biosynthesis, and (b) it facilita...