A Breakdown in the LDL 
System Can Now Be Treated 
The low-density lipoprotein system works like 
a thermostat to ensure that the cell always 
has enough cholesterol for life and growth, 
without accumulating too much of it. Because 
of a defective gene, however, the cells of 
people with familial hypercholesterolemia 
(FH) are severely deficient in LDL receptors. 
This breaks the cells' normal chain of control 
and leads to over-production of cholesterol by 
the liver. The liver manufactures cholesterol 
and releases it into the blood, but since the 
cells do not have enough LDL receptors, not 
enough cholesterol is taken up. Instead it 
begins to clog the arteries. 
People who have two genes for FH suffer 
from heart disease from a very early age, 
sometimes as early as age 1 . Persons with 
only one defective gene do make some LDL 
receptors, but still have a high risk of heart 
attacks, and often have an attack before 
age 30. FH is a relatively common genetic 
disorder; as many as 1 person in 500 carries 
one copy of the defective gene. 
Michael Brown and Joseph Goldstein of 
the University of Texas Health Science Center 
at Dallas elucidated both the precise genetic 
defects and the role of the LDL receptor in FH. 
In 1985, both men were awarded Nobel 
Prizes for this work. Their studies also led to 
the development of lovastatin, a drug to treat 
FH. Lovasfatin has a dual action: it damps 
down the liver's ability to manufacture 
cholesterol so that fewer LDL's enter the 
bloodstream, and it causes the LDL receptors 
that the person has to take up cholesterol 
more efficiently. 
The mechanism Brown and Goldstein 
outlined for LDL receptors is but one example 
of the process of receptor-mediated endocy- 
tosis. The cell also uses protein receptors to 
take in such substances as insulin, transferrin 
(an iron-bearing compound), and cell 
complexes that are produced when the 
immune system is activated. 
