Brown, Goldstein and the LDL receptor

Familial hypercholesterolemia is inherited as a dominant trait. About 1 in 500 people carry one mutant gene; their LDL is doubled from birth and heart attacks begin at 30 to 40. About 5 percent of people who have a heart attack before age 60 have this form. Roughly 1 in a million inherit two copies. Their LDL is six to ten times normal, and they often have heart attacks in childhood.

Michael Brown and Joseph Goldstein began studying the disease in 1972 at the University of Texas Southwestern Medical School in Dallas. Cholesterol handling was thought to happen mainly in the liver and gut, and the livers of patients could not be studied, so they grew skin fibroblasts in culture and built a micro-assay for HMG CoA reductase, the enzyme that limits the rate of cholesterol synthesis. In normal cells, taking lipoproteins out of the medium raised its activity at least 50-fold in 24 hours, and adding them back shut it down. LDL did this; HDL did not. That specificity was their first hint of a receptor.

In 1973 they reported that fibroblasts from three unrelated patients with the severe, two-copy form had 40 to 60 times normal reductase activity, because LDL could not switch the enzyme off, and that the cells overproduced cholesterol. The enzyme itself behaved normally. Cells from two parents who carried one copy fell in between. They went on to show that normal cells bind LDL to a receptor in coated pits on the cell surface and pull it inside, a process now called receptor-mediated endocytosis. Cells from the severe form lacked working receptors, and cells from the milder form had about half the normal number. When cells take in cholesterol they make fewer receptors, leaving more LDL in the blood.

The receptor pointed to treatment. In patients with the milder form, the drugs cholestyramine and mevinolin raised the number of receptors and lowered blood cholesterol. Patients with the severe form have no functional receptors to raise, and liver transplantation was tried instead: a 6-year-old girl who had already had several heart attacks received a new heart and liver together, and her total plasma cholesterol fell from 1,100 mg/dl to between 200 and 300 mg/dl. Brown and Goldstein shared the 1985 Nobel Prize in Physiology or Medicine.