Hallelujah Moments by Cordes Eugene H

Author:Cordes, Eugene H.
Language: eng
Format: epub
Publisher: Oxford University Press, USA
Published: 2013-04-23T04:00:00+00:00

The Low-Density Lipoprotein Receptor Is a Key Player in the Regulation of Cholesterol Metabolism

Two biomedical scientists at the Southwestern Medical School in Dallas, Texas—Michael Brown and Joseph Goldstein—pretty much figured out how cholesterol metabolism is regulated. They shared the Nobel Prize in Physiology or Medicine in 1985 for their work.

Brown and Goldstein got started through the study of a disease known as familial hypercholesterolemia (FH). As the name implies, this is a genetic disease, one that is inherited from one’s parents. Also, as the name implies, patients with FH have too much cholesterol in their blood, which is not a good thing. The genetic defect causing FH is in the gene encoding the receptor for low-density lipoproteins (LDLs), often referred to as bad cholesterol. Brown and Goldstein discovered the LDL receptor, and it is the star of this part of the story.

Here is the critical experiment that led Brown and Goldstein to the LDL receptor. Human skin fibroblasts in cell culture make cholesterol. When the cells are grown in a simple protein-free medium, the rate of cholesterol synthesis is high. When human serum (blood from which red cells and clotting proteins have been removed) is added, the rate of cholesterol synthesis is much reduced. Brown and Goldstein demonstrated that the inhibitory factor in human serum is LDL. To inhibit cholesterol synthesis in the cells, the LDL must get in. This work generated the idea of an LDL receptor, a protein that binds LDL and internalizes it in the cells.

Brown and Goldstein repeated this experiment with cells taken from patients with FH. As with cells from healthy people, FH cells show a high rate of cholesterol synthesis in the absence of human serum. However, the rate of cholesterol synthesis is not reduced in FH cells by the addition of serum-containing LDL. The rate of cholesterol synthesis in FH cells is reduced by the addition of pure cholesterol.

These experiments tell us the following. In cells from healthy people, the LDL receptor takes up LDL from the medium, and the associated cholesterol inhibits cholesterol synthesis. The cells from patients with FH must have a defective LDL receptor because LDL itself does not inhibit cholesterol synthesis but the cells still respond to cholesterol itself.

FH comes in two guises. You have two genes, one on each chromosome 19, that encode the LDL receptor, a protein. If one of these genes is flawed and one is normal, you are a heterozygote for FH. This is a rather common genetic disease; about one person in 500 is an FH heterozygote. These people have half the number of LDL receptors and about twice as much LDL cholesterol in their blood as people with two good genes. The consequence is not good; many have heart attacks in their 30s or 40s. If both copies of the gene for the LDL receptor are flawed, you are an FH homozygote, have no functional LDL receptors, and have an extremely high blood LDL concentration. FH homozygotes may have a heart attack by age 10.

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