The LDL receptor

Abstract

In this article, the history of the LDL receptor is recounted by its codiscoverers. Their early work on the LDL receptor explained a genetic cause of heart attacks and led to new ways of thinking about cholesterol metabolism. The LDL receptor discovery also introduced three general concepts to cell biology: receptor-mediated endocytosis, receptor recycling, and feedback regulation of receptors. The latter concept provides the mechanism by which statins selectively lower plasma LDL, reducing heart attacks and prolonging life.

Figure 1

A 10-year-old girl with homozygous FH. Note the elevated orange-yellow xanthomas lying superficially over the knees, the wrists, and interdigital webs. These xanthomas arise from the deposition of plasma LDL-derived cholesterol into macrophages of the skin. The rate of deposition is proportional to the severity and duration of the elevation in plasma LDL. A similar deposition of LDL-derived cholesterol occurred in the coronary arteries of this girl, producing atheromas of artery wall, which led to her first myocardial infarction at age 8.

Figure 2

Regulation of HMG CoA reductase activity in fibroblasts from a normal subject and from an FH homozygote. A, Monolayers of cells were grown in dishes containing 10% fetal calf serum. On day 6 of cell growth (zero time), the medium was replaced with fresh medium containing 5% human serum from which the lipoproteins had been removed. At the indicated time, extracts were prepared, and HMG CoA reductase activity was measured. B, 24 hours after addition of 5% human lipoprotein-deficient serum, human LDL was added to give the indicated cholesterol concentration. HMG CoA reductase activity was measured in cell free extracts at the indicated time. (Modified from 8).

Figure 3

Internalization and degradation at 37° C of ¹²⁵I-LDL by fibroblasts from a normal subject (A) and from J.D., a patient with the internalization-defective form of FH (B). Each cell monolayer was allowed to bind ¹²⁵I-LDL (10 μg protein/ml) at 4° C for 2 hours, after which the cells were washed extensively. In one set of dishes, the amount of ¹²⁵I-LDL bound was determined by measuring the amount of ¹²⁵I-LDL that could be released from the surface by treatment with heparin. Replicate dishes then received warm medium and were incubated at 37° C. After the indicated interval, the dishes were rapidly chilled to 4° C, and the amounts of surface-bound (heparin-releasable) ¹²⁵I-LDL, internalized (heparin-resistant) ¹²⁵I-LDL, and degraded (trichloroacetic acid-soluble) ¹²⁵I-LDL were measured. (Modified from 27).

Figure 4

Sequential steps in the LDL receptor pathway of mammalian cells (already defined in text). (Modified from 58).

Figure 5

Actions attributable to the LDL receptor in fibroblasts from a normal subject and from a homozygote with the receptor-negative form of FH . Cells were incubated with varying concentrations of ¹²⁵I-LDL or unlabeled LDL at 37° C for 5 hours and assayed as described . All data are normalized to 1 mg of total cell protein. The units for each assay are as follows: Binding, μg of ¹²⁵I-LDL bound to cell surface; Internalization, μg of ¹²⁵I-LDL contained within the cell; Hydrolysis of apoprotein B-100, μg of ¹²⁵I-LDL degraded to ¹²⁵I-monoiodotyrosine per hour; Hydrolysis of cholesteryl esters, nmol of [³H]cholesterol formed per hour from the hydrolysis of LDL labeled with [³H]cholesteryl linoleate; Cholesterol synthesis, nmol of [¹⁴C]acetate incorporated into [¹⁴C]cholesterol per hour by intact cells; Cholesterol esterification, nmol of [¹⁴C]oleate incorporated into cholesteryl [¹⁴C]oleate per hour by intact cells. (Modified from 58).

Figure 6

Joseph L. Goldstein (left) and Michael S. Brown on the day of announcement of their Nobel Prize in Physiology or Medicine on October 15, 1985.